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ABC transporter

ABC transporters, also known as ATP-binding cassette transporters, are a large superfamily of integral membrane proteins that harness the energy from ATP hydrolysis to actively transport diverse substrates, including ions, amino acids, peptides, sugars, lipids, steroids, and xenobiotics, across cellular membranes in both inward (import) and outward (export) directions.^[1] These proteins are ubiquitously expressed across all domains of life, from bacteria to humans, and are essential for maintaining cellular homeostasis by facilitating nutrient uptake, detoxification, and the extrusion of harmful substances.^[2] In humans, the ABC superfamily consists of 48 distinct genes organized into seven subfamilies (ABCA through ABCG), many of which function as full transporters with four core domains or as half transporters that dimerize to form functional units.^[3] The basic architecture of ABC transporters includes two transmembrane domains (TMDs) that form the substrate-binding pathway and two nucleotide-binding domains (NBDs) located intracellularly, where ATP binding and hydrolysis drive conformational changes to enable the alternating access mechanism of transport.^[1] This mechanism involves an inward-facing state for substrate binding, followed by ATP-induced dimerization of the NBDs to switch to an outward-facing conformation for release, with hydrolysis resetting the cycle.^[1] Structural studies, such as those on bacterial importers like BtuCD (for vitamin B12) and exporters like Sav1866, have elucidated these dynamics, revealing a conserved core fold despite functional diversity.^[1] ABC transporters play pivotal roles in physiology and pathology; for instance, they mediate lipid transport in the ABCA subfamily (e.g., ABCA1 in cholesterol efflux to HDL particles) and bile acid handling in the ABCB and ABCC subfamilies.^[3] In pharmacology, prominent members like P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1), and breast cancer resistance protein (ABCG2) contribute to multidrug resistance in cancer by effluxing chemotherapeutic agents, impacting drug bioavailability and therapeutic efficacy.^[2] Mutations in ABC genes underlie at least 21 human genetic disorders, including cystic fibrosis (ABCC7/CFTR), Tangier disease (ABCA1), and Dubin-Johnson syndrome (ABCC2), highlighting their clinical significance.^[3] Overall, these transporters exemplify the power of ATP-driven molecular machines in cellular adaptation and survival.^[1]

Overview and Discovery

Historical Background

The recognition of ATP-binding sites in bacterial membrane transport systems began in the 1970s, with early studies on the histidine permease of Salmonella typhimurium demonstrating energy dependence through ATP hydrolysis, and nucleotide-binding capability identified in the early 1980s, marking the first identification of what would become known as an ABC transporter. This periplasmic transport system, responsible for high-affinity histidine uptake, laying the groundwork for understanding ATP-powered import mechanisms in prokaryotes. Independently, in the same year, Juliano and Ling discovered a 170-kDa surface glycoprotein in multidrug-resistant Chinese hamster ovary cells, termed P-glycoprotein (MDR1 or ABCB1), which was linked to the efflux of diverse chemotherapeutic agents and represented the initial eukaryotic example of such a transporter. Cloning efforts in the early 1980s expanded this field significantly, with the histidine permease genes (hisP, hisQ, and hisM) sequenced in 1982, revealing conserved ATP-binding domains across bacterial transport systems. By 1985, the human MDR1 gene was cloned, confirming P-glycoprotein's role in mammalian multidrug resistance. These discoveries culminated in the 1986 proposal by Higgins and colleagues of a superfamily of related proteins, unified by homologous nucleotide-binding folds involved in ATP utilization for transport. The term "ATP-binding cassette" (ABC) was formally coined by Higgins in 1992 to describe the characteristic cassette of conserved motifs—Walker A, Walker B, and the ABC signature sequence—that define this superfamily. Structural biology milestones accelerated characterization in the 2000s and beyond. In 2006, the crystal structure of the bacterial exporter Sav1866 from Staphylococcus aureus was solved at 3 Å resolution, offering the first atomic view of an ABC transporter in an outward-facing conformation and illuminating the architecture of transmembrane and nucleotide-binding domains. The advent of cryo-electron microscopy in the early 2020s enabled breakthroughs for human orthologs, including the 2020 structure of full-length ABCB6 in an apo inward-facing state and the 2022 structures of ABCA7 in nucleotide-bound conformations, which captured dynamic transitions essential for substrate translocation. These advances have provided critical insights into conformational cycles across the ABC family.

General Function and Classification

ABC transporters constitute a large superfamily of membrane proteins that harness the energy from ATP hydrolysis to actively transport a diverse array of substrates, including ions, amino acids, peptides, sugars, lipids, steroids, and xenobiotics, across lipid bilayers in an ATP-dependent manner.^[4] This primary active transport enables the movement of these substrates against their electrochemical or concentration gradients, playing essential roles in nutrient uptake, detoxification, lipid homeostasis, and antigen presentation.^[5] The core mechanism involves two transmembrane domains (TMDs) that form the substrate pathway and two nucleotide-binding domains (NBDs) that couple ATP binding and hydrolysis to conformational changes driving transport.^[4] ABC transporters are broadly classified into three main functional categories based on their directionality and roles: importers, exporters, and non-canonical members. Importers, predominantly found in prokaryotes and archaea, facilitate the uptake of essential nutrients such as vitamins, amino acids, and peptides from the extracellular environment into the cytoplasm, often in conjunction with periplasmic binding proteins.^[4] Exporters, present across all domains of life, mediate the efflux of a wide range of substrates, including toxins, drugs, bile salts, and lipids, from the cytoplasm to the extracellular space or into organelles, contributing to cellular detoxification and multidrug resistance.^[5] Non-canonical ABC proteins, such as those in the ABCE and ABCF subfamilies, lack TMDs and do not perform transport functions; instead, they participate in processes like ribosome biogenesis, translation initiation, and inhibition of ribonuclease L, highlighting the superfamily's versatility beyond membrane translocation.^[5] These proteins are ubiquitously distributed across all three domains of life—Bacteria, Archaea, and Eukarya—reflecting their ancient evolutionary origins, with the human genome encoding 48 ABC genes organized into seven subfamilies (A–G), of which 44 produce functional membrane transporters.^[6] In contrast, bacterial genomes often contain a higher proportion of ABC-related genes relative to genome size; for example, Escherichia coli has approximately 80 ABC proteins, representing about 2% of its proteome.^[4] A hallmark of evolutionary conservation in this superfamily is the Walker A and Walker B motifs within the NBDs, which are highly preserved sequences (Walker A: GXXGXGK(S/T); Walker B: φφφφDE) essential for ATP binding, hydrolysis, and dimerization, enabling the identification of new family members through sequence homology.^[4] Unlike other ATP-powered transporters such as P-type ATPases, which rely on autophosphorylation of an aspartate residue to drive ion transport (e.g., Na⁺/K⁺-ATPase), ABC transporters depend on the modular interaction between their ABC-specific NBDs and TMDs without forming covalent phospho-intermediates, utilizing direct ATP hydrolysis to power an alternating access mechanism.^[4] This structural and mechanistic distinction underscores the ABC superfamily's unique adaptability for diverse substrates across cellular compartments.^[5]

Structure and Domains

Transmembrane Domains

The transmembrane domains (TMDs) of ABC transporters form the membrane-embedded core responsible for substrate recognition and translocation across lipid bilayers. Each TMD typically consists of 6 to 10 transmembrane α-helices per monomer, arranged into a bundle that creates a central cavity or pocket for substrate binding.^[7] In full-length transporters, which are the most common architecture, the TMDs dimerize to form a symmetric or pseudo-symmetric structure, with each monomer contributing its helical bundle to generate a shared translocation pathway.^[7] Structural variability in TMDs distinguishes ABC importers from exporters. Importer TMDs generally couple with extracellular substrate-binding proteins (SBPs) that deliver hydrophilic substrates to a high-affinity entry site on the periplasmic or extracellular face, often requiring 8–10 helices per TMD to accommodate this interaction.^[8] In contrast, exporter TMDs feature an inward-facing conformation with a deep pocket accessible from the cytoplasm, typically built from 6 helices per TMD, enabling the capture and extrusion of hydrophobic or amphipathic substrates directly through the membrane.^[7] A classic example is the bacterial lipid flippase MsbA, where each monomer's TMD comprises 6 helices, dimerizing to form a 12-helix bundle that facilitates phospholipid translocation from the inner to the outer leaflet.^[9] Substrate specificity in TMDs arises from conserved and variable residues lining the binding pocket. In exporters, aromatic residues such as phenylalanines and tyrosines within the helical bundles often mediate π-π stacking and hydrophobic interactions with drug-like substrates, contributing to broad polyspecificity in transporters like P-glycoprotein.^[10] These residues cluster in the pocket's core, adapting to diverse ligands while maintaining overall fold integrity. Recent cryo-EM structures resolved after 2018 have illuminated dynamic TMD rearrangements essential for the transport cycle. For instance, in MsbA and human ABCG2, nucleotide-induced dimerization of the associated nucleotide-binding domains (NBDs) triggers rigid-body rotations and twisting of TMD helices, transitioning the pocket from inward- to outward-facing orientations to drive substrate release.^[11] These studies reveal how interdomain coupling propagates conformational changes through intracellular loops connecting TMDs to NBDs, ensuring coordinated gating without ATP hydrolysis details.^[12]

Nucleotide-Binding Domains

The nucleotide-binding domains (NBDs) of ABC transporters are highly conserved cytosolic modules responsible for binding and hydrolyzing ATP to provide energy for transport. Each NBD consists of two main subdomains: a RecA-like subdomain that forms the core ATP-binding site and a helical subdomain that covers the nucleotide-binding pocket. The RecA-like subdomain shares structural homology with the RecA protein involved in DNA repair, featuring a fold common to many ATPases. The helical subdomain, unique to the ABC family, contributes to ATP coordination and allosteric regulation.^[13] Central to ATP binding are the Walker A and Walker B motifs within the RecA-like subdomain. The Walker A motif, also known as the P-loop, is a glycine-rich sequence (GXXGXGKS/T) that interacts with the phosphate groups of ATP and coordinates a magnesium ion essential for nucleotide positioning. The Walker B motif, typically comprising a conserved aspartate and hydrophobic residues (hhhD, where h is hydrophobic), facilitates magnesium coordination and participates in ATP hydrolysis by polarizing a water molecule for nucleophilic attack. Additionally, the ABC family-specific signature sequence (LSGGQ or C-motif) in the helical subdomain of one NBD interacts with the Walker A motif of the opposing NBD, enabling ATP sandwiching at the dimer interface and promoting domain dimerization. This motif is absent in most other ATPases, distinguishing ABC NBDs.^[14]^[15] In ABC exporters, the two NBDs typically form a head-to-tail dimer even in the absence of ATP, with the signature sequence of one NBD closely apposed to the Walker A of the other, facilitating rapid ATP binding at the interface. In contrast, NBDs in ABC importers remain separated until ATP binding induces dimerization, which is crucial for coupling energy to substrate import. Mutations in NBDs often disrupt ATP binding or hydrolysis, leading to disease; for example, the G551D mutation in the signature sequence of NBD1 in human CFTR (ABCC7) impairs ATP-dependent gating, causing cystic fibrosis by reducing chloride channel activity.^[16]^[17] High-resolution structural insights into NBDs began with X-ray crystallography of the MJ0796 NBD from the archaeal importer in Methanocaldococcus jannaschii, revealing the RecA-helical architecture and ATP-binding pocket at 2.7 Å resolution.^[18] Subsequent studies confirmed the head-to-tail dimer and ATP sandwiching in both importer and exporter NBDs. Advances in cryo-electron microscopy have provided atomic models of full ABC assemblies in the 2020s, illustrating NBD conformations in various nucleotide states and their interactions with transmembrane domains. As of 2025, additional high-resolution cryo-EM structures, including those of the zinc importer ZnuBC and MsbA in multiple environments, have further elucidated these interactions.^[19]^[20]

Domain Interactions and ATP Hydrolysis

The transmembrane domains (TMDs) of ABC transporters interact with the nucleotide-binding domains (NBDs) primarily through intracellular loops (ICLs), which form the core of the transmission interface responsible for signal transduction between these domains. In particular, ICL1 and ICL2 in the TMDs extend into the cytoplasm and engage with specific surfaces on the NBDs, often via coupling helices that create ball-and-socket-like joints, enabling the mechanical coupling of conformational changes. This interface ensures that movements in the NBDs are transmitted to the TMDs, facilitating the alternating access mechanism essential for substrate translocation. Seminal structural studies, such as the crystal structure of the bacterial exporter Sav1866, have revealed how these ICL-NBD contacts position the NBDs to respond to nucleotide states while maintaining TMD integrity.^[21] The ATP hydrolysis cycle in ABC transporters is tightly coupled to domain interactions, where ATP binding at the NBD interface promotes dimerization into a closed conformation, bringing the two NBDs together and stabilizing the transmission interface. This dimerization transmits a signal through the ICLs to the TMDs, inducing an outward-facing conformation that exposes the substrate-binding site to the extracellular or periplasmic side. Subsequent ATP hydrolysis at the NBD dimer interface generates inorganic phosphate (Pi) and ADP, leading to NBD dissociation into an open state; this dissociation relaxes the transmission interface, allowing the TMDs to switch to an inward-facing conformation and reset the transporter. The energy released from this hydrolysis, represented by the reaction ATP + H₂O → ADP + Pᵢ, provides approximately ΔG ≈ -30 kJ/mol under physiological conditions, which powers the conformational switch against the electrochemical gradient.^[22]^[23] Many ABC transporters exhibit asymmetry in their NBDs, featuring a consensus site with high hydrolytic activity and a degenerate site that hydrolyzes ATP less efficiently or not at all, influencing the timing and coordination of the hydrolysis cycle. In such cases, the consensus site initiates rapid ATP cleavage to drive initial TMD reconfiguration, while the degenerate site may bind ATP without hydrolysis to maintain partial dimer stability, ensuring unidirectional transport. This asymmetry arises from sequence variations, such as in the Walker B motif, and has been observed in structures of heterodimeric exporters like P-glycoprotein (P-gp).^[24]^[25] Inhibitors often target the NBD-TMD interfaces to disrupt these interactions; for instance, verapamil binds near the ICL regions of P-gp, allosterically modulating the transmission interface and inhibiting ATP-driven conformational changes without directly blocking the nucleotide sites. This binding stabilizes inward-facing states, reducing transport efficiency and highlighting the interface's role as a regulatory hotspot. Structural analyses of P-gp have confirmed such allosteric sites at the ICL-NBD contacts, underscoring their therapeutic potential in overcoming multidrug resistance.^[26]^[27]

Transport Mechanisms

Core Mechanism of ATP-Driven Transport

ABC transporters employ a conserved alternating access mechanism to drive substrate translocation across biological membranes, powered by the binding and hydrolysis of ATP at their nucleotide-binding domains (NBDs). In this model, the transporter alternates between inward-facing and outward-facing conformations, enabling selective access to substrates from one side of the membrane while occluding the other. For exporters, the cycle begins in an inward-facing state where substrates bind from the cytoplasm; ATP binding triggers a switch to an outward-facing conformation for release. Conversely, importers start in an outward-facing state to capture substrates from the extracellular or periplasmic space, transitioning inward upon ATP action. This universal framework couples ATP-driven movements of the NBDs to conformational changes in the transmembrane domains (TMDs), ensuring directional transport without direct ATP hydrolysis at the substrate-binding site.^[28]^[4] The transport cycle initiates with ATP binding to the separated NBDs, inducing their dimerization in a head-to-tail arrangement where the nucleotide cleft closes, sandwiching two ATP molecules at the interface. This dimerization generates a power stroke that transmits force through intracellular coupling helices to the TMDs, twisting and reorienting them to flip the substrate-binding cavity across the membrane. The closed NBD dimer stabilizes the access-switched state, facilitating substrate occlusion and translocation. Structural studies of bacterial exporters like Sav1866 and MsbA confirm that NBD closure correlates with TMD outward opening, with the energy from ATP binding (~25 kJ/mol stabilization) driving these rigid-body movements.^[4] Subsequent ATP hydrolysis at the consensus nucleotide-binding site disrupts the dimer, promoting NBD separation and resetting the TMDs to the initial conformation. This step involves ADP release followed by inorganic phosphate (Pi) ejection, which is often the rate-limiting process in the cycle, allowing the transporter to prepare for the next round of substrate binding. The hydrolysis provides the thermodynamic driving force, with the reaction free energy near zero in the protein environment, ensuring efficient energy transduction without wasteful dissipation. Biochemical assays on isolated NBDs and full transporters demonstrate that both NBDs are required for hydrolysis, underscoring the coordinated nature of the cycle.^[29]^[28] Spectroscopic techniques, including fluorescence resonance energy transfer (FRET) and double electron-electron resonance (DEER), have provided direct evidence for these dynamics, revealing NBD separations of approximately 1-3 nm in the apo state that close upon ATP binding, alongside TMD rearrangements opening the extracellular gate. For instance, DEER on P-glycoprotein showed asymmetric NBD closing and TMD twisting in the transition state, supporting the power stroke model. These studies highlight the mechanical coupling essential for alternating access.^[30]^[31]^[32] Certain non-transporting ABC proteins, such as ABCE, exploit a similar ATP hydrolysis cycle to mediate protein-protein interactions rather than membrane translocation; for example, ABCE uses NBD dimerization to associate with ribosomes during translation initiation and termination. This adaptation illustrates the versatility of the core ATP-driven mechanism beyond transport functions.^[4]

Importer-Specific Mechanisms

ABC importers exhibit specialized mechanisms to capture and translocate substrates from the extracellular environment into the cytoplasm, primarily relying on substrate-binding proteins (SBPs) that operate in conjunction with the transmembrane domains (TMDs) and nucleotide-binding domains (NBDs). In Type I importers, the SBP binds the substrate with high affinity in the periplasm or extracellular space, then docks to the outward-facing TMDs of the transporter, forming a high-affinity complex that positions the substrate near the translocation pathway. Upon ATP binding to the NBDs, the substrate is released from the SBP into the TMD lumen, and the SBP subsequently dissociates, allowing it to bind new substrate molecules; this process ensures efficient recycling of the SBP, which is often present in excess relative to the transporter.^[33]^[34] Type II importers, in contrast, feature SBPs that maintain a tighter, more persistent association with the TMDs throughout much of the transport cycle, reflecting adaptations for larger or more hydrophilic substrates such as vitamins. For instance, in the vitamin B12 importer BtuCDF from Escherichia coli, the SBP BtuF exhibits an exceptionally high affinity (K_d ≈ 15 nM) for its substrate and remains bound even after delivery, potentially requiring multiple rounds of ATP hydrolysis to fully dissociate and reset the system. This stable SBP-TMD interaction contrasts with the transient docking in Type I systems and supports the import of bulky molecules like cobalamin by stabilizing the outward-facing conformation until energy input drives translocation. Kinetic studies indicate that such mechanisms yield apparent K_m values in the low nanomolar range for nutrient uptake, underscoring the high sensitivity of these transporters to substrate availability.^[33]^[35]^[36]^[37] A key importer-specific adaptation is the power stroke mechanism, where NBD dimerization upon ATP binding induces a conformational change in the TMDs, transitioning from an outward-open to an inward-open state and effectively scooping the substrate across the membrane. This builds on the general alternating access model but is tailored for import by coupling SBP-mediated delivery to the inward-directed motion, preventing backflow and ensuring unidirectional transport. The E. coli maltose importer MalEFGK_2 exemplifies this, with the SBP MalE binding maltose (K_d ≈ 1 μM) and docking to the heterodimeric TMD (MalF-MalG) before ATP-driven NBD (MalK_2) dimerization releases the sugar cytoplasmically; post-import, MalE dissociates, and hydrolysis resets the cycle, with transport kinetics showing K_m values around 1 μM but approaching nanomolar affinities under saturating SBP conditions. Overall, these mechanisms highlight how ABC importers achieve selective, energy-efficient uptake of scarce nutrients.^[34]^[38]^[39]

Exporter-Specific Mechanisms

ABC exporters initiate transport in an inward-facing conformation, where substrates access binding pockets within the transmembrane domains (TMDs) from the cytosol. These pockets, often hydrophobic and located midway through the membrane bilayer, exhibit high affinity for diverse substrates, enabling initial recognition and sequestration. For instance, in the bacterial lipid flippase MsbA, the inward-open state features a large cavity formed by transmembrane helices that accommodates lipid A precursors via interactions with elbow helices.^[40] Similarly, in eukaryotic exporters like P-glycoprotein (ABCB1), the TMDs form a flexible, polyspecific binding site that captures hydrophobic substrates through van der Waals and electrostatic interactions.^[41] Upon ATP binding to the nucleotide-binding domains (NBDs), the exporter undergoes a conformational flip to an outward-facing state, powered by NBD dimerization that transmits mechanical force through intracellular coupling helices to rearrange the TMDs. This transition exposes the substrate-binding pocket to the extracellular or periplasmic space, facilitating release. The process shares the core ATP hydrolysis cycle with other ABC transporters but is adapted in exporters to ensure unidirectional export. In MsbA, cryo-EM structures reveal how ATP binding separates the TMDs extracellularly, promoting lipid translocation from the inner to outer leaflet in a flippase-like manner.^[40] For hydrophilic drugs, such as those transported by ABCB1, the mechanism resembles channel-like passage, where the reoriented TMDs allow solvent-accessible release without full membrane traversal.^[41] Polyspecificity arises from the inherent flexibility of TMD binding sites, which can accommodate a wide array of chemically diverse substrates including steroids, peptides, and xenobiotics. In ABCB1, this is exemplified by its ability to bind over 300 compounds, ranging from vinblastine to verapamil, through adaptable interactions across multiple transmembrane helices that adjust to substrate size and polarity. The peptide exporter TAP (ABCB2/3) similarly uses a promiscuous groove to handle antigenic peptides of varying lengths.^[40]^[41] Following ATP hydrolysis, the NBDs separate, stabilizing an outward-open state with low substrate affinity that promotes dissociation and prevents backflow into the cytosol. This post-hydrolysis conformation, observed in structures like that of MsbA (PDB: 3B60), features widely separated TMDs extracellularly, ensuring irreversible export while ADP and phosphate release resets the transporter to the inward-facing ground state.^[40] Allosteric regulation fine-tunes these dynamics, often through substrate-induced acceleration of NBD dimerization. In ABCB1, substrate binding allosterically enhances ATPase activity up to 10-fold by stabilizing interactions between the Q-loop and intracellular loops, thereby coupling occupancy to transport efficiency. Similar substrate-driven allostery in MsbA coordinates lipid insertion with nucleotide binding.^[40]^[41]

ABC Importers

Prokaryotic Large Importers

Prokaryotic large ABC importers, classified as Type I systems, are complex, multi-subunit transporters that enable bacteria to acquire scarce nutrients through high-affinity binding and ATP-driven translocation across the inner membrane. These systems are prevalent in Gram-negative bacteria and consist of a periplasmic substrate-binding protein (SBP), a dimer of transmembrane domains (TMDs) each spanning 5-6 helices (totaling 10-12 transmembrane helices), and a homodimeric pair of nucleotide-binding domains (NBDs) that couple ATP hydrolysis to transport. The SBP captures substrates in the periplasm, docks to the TMDs to deliver them, and the NBDs power the conformational changes necessary for import.^[33] The typical stoichiometry of these importers is 1-2 SBPs : 2 TMDs : 2 NBDs, which supports efficient substrate handover and energy utilization while minimizing cellular resource demands. This architecture allows for specificity toward diverse substrates, including amino acids, iron-siderophore complexes, and polysaccharides, essential for survival in nutrient-limited niches. Genes for these components are frequently clustered in operons, such as those encoding SBP-TMD-NBD modules, promoting coordinated expression and assembly; in pathogens like Escherichia coli, these operons underpin virulence by facilitating nutrient scavenging during host colonization.^[33]^[42]^[43] A classic example is the histidine permease (HisJQP₂) in E. coli and Salmonella typhimurium, where the SBP HisJ (~28 kDa) binds histidine and related amino acids before interacting with the HisQ₂P₂ TMD-NBD complex to drive uptake. For iron acquisition, systems like FhuCDB import ferrichrome-iron complexes via the SBP FhuD, enabling bacteria to compete for iron in hostile environments. Polysaccharide import is exemplified by the maltose system (MalFGK₂), with the larger SBP MalE (~43 kDa) binding maltodextrins to support carbon source utilization.^[44]^[45]^[46]^[36] Recent studies from the 2020s on iron import in anaerobic or facultative anaerobic bacteria, such as the IrtAB importer in Mycobacterium tuberculosis, have revealed oxygen-sensitive regulation and mechanisms, where low-oxygen conditions enhance siderophore uptake to maintain iron homeostasis, underscoring adaptations for microaerobic niches during infection. The importer mechanism involves transient SBP docking to the TMDs, which induces an inward-facing conformation for substrate release and translocation.^[47]^[48]

Prokaryotic Small Importers

Prokaryotic small ABC importers, classified as Type II and Type III systems, facilitate the uptake of small molecules such as peptides and metals through compact architectures featuring minimal or fused substrate-binding proteins (SBPs). Type II importers utilize small, extracytoplasmic SBPs that are typically anchored to the membrane via lipid modifications in Gram-positive bacteria, enabling efficient capture of substrates like oligopeptides in nutrient-scarce environments.^[33] These SBPs exhibit sizes around 20-30 kDa, which confers higher mobility and allows for broader substrate specificity compared to the larger SBPs in Type I systems.^[35] In contrast, Type III importers, often referred to as ECF-type (energy-coupling factor), incorporate fused SBPs directly linked to the transmembrane domains (TMDs), streamlining the transport of trace metals and vitamins without requiring separate soluble binding components.^[33] A representative example of a Type II small importer is the oligopeptide permease (Opp) system, prevalent in Gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus, where the SBP OppA binds di- and tripeptides with high affinity before delivering them to the membrane-embedded OppBCDF complex for ATP-driven translocation.^[49] The Opp system not only supports peptide nutrition but also plays a critical role in quorum sensing by importing signaling peptides that regulate processes like competence and virulence.^[49] For metal uptake, the ABC transporter encoded by the abcABCD gene cluster in Helicobacter pylori exemplifies a small importer essential for nickel acquisition, where nickel ions are transported to activate urease, enabling survival in the acidic gastric environment; mutations in abcC or abcD reduce urease activity by over 85%, severely impairing colonization.^[50] Mechanistically, these small importers rely on adaptations that promote direct substrate handover from the SBP to the TMDs without the large-scale conformational shifts observed in Type I systems. In Type II importers, the SBP forms a stable, locked complex with the importer upon ATP binding, facilitating substrate release through minimal structural rearrangements in the SBP—often limited to rigid-body rotations of less than 10°—which enhances efficiency for low-abundance substrates.^[35] This contrasts with the Venus flytrap-like closure in larger SBPs, allowing Type II systems to maintain broad specificity while conserving energy.^[33] Type III fused systems further optimize this by integrating the SBP domain, enabling rapid, coupled delivery of metals like nickel or cobalt directly into the translocation pathway.^[35] Evolutionarily, prokaryotic small ABC importers share ancestral motifs with eukaryotic peptide transporters, particularly in the nucleotide-binding domains, suggesting horizontal gene transfer or common origins that facilitated the adaptation of peptide uptake mechanisms across kingdoms.^[51] Model bacteria like Escherichia coli and B. subtilis encode approximately 20-40 ABC importer genes, with small systems comprising a significant portion dedicated to essential micronutrients, underscoring their prevalence in prokaryotic genomes for survival in diverse niches.^[52]

Eukaryotic Importers

In eukaryotes, ABC importers are far less abundant than in prokaryotes and are primarily adapted for intracellular or organellar transport rather than direct uptake from the extracellular environment. Unlike bacterial importers that rely on soluble binding proteins (SBPs) for substrate capture, eukaryotic counterparts lack dedicated extracellular SBPs and instead depend on vesicular trafficking mechanisms to deliver substrates to the transporter sites. This adaptation reflects the compartmentalized nature of eukaryotic cells, where ABC importers often facilitate the movement of lipids, ions, or metabolites into organelles such as chloroplasts or endosomal structures.^[51] In lower eukaryotes like algae and primitive plants, bona fide ABC importers resembling bacterial Type I and Type II systems have been identified, mainly in photosynthetic organelles. For instance, in the green alga Chlamydomonas reinhardtii, a Type I importer complex (CysT, CysW, CysA, CysP) transports sulfate into chloroplasts to support cysteine and methionine biosynthesis essential for amino acid production. Similarly, Type II importers in the red alga Cyanidioschyzon merolae and glaucophyte Cyanophora paradoxa are proposed to import transition metals like manganese or zinc, based on homology to bacterial vitamin B12 importers, aiding in cofactor assembly for photosynthetic proteins. These systems highlight the endosymbiotic origin of eukaryotic importers, retained in autotrophic lineages but largely lost in non-photosynthetic higher eukaryotes.^[51] In plants, the ABCI subfamily exemplifies eukaryotic importers localized to the chloroplast inner envelope, where they import essential lipids for thylakoid membrane biogenesis. The TRIGALACTOSYLDIACYLGLYCEROL (TGD) complex, comprising TGD1 (AtABCI13), TGD2 (AtABCI14), and TGD3 (AtABCI15), functions as a non-vesicular lipid importer, transferring phosphatidic acid and other phospholipids from the endoplasmic reticulum to the chloroplast via ER-plastid contact sites. Mutations in these genes disrupt lipid trafficking, leading to altered chloroplast galactolipid composition and impaired photosynthesis, underscoring their role in maintaining organelle membrane homeostasis.^[53] In mammals, ABC importers are repurposed for endosomal and lysosomal functions, with notable examples in lipid handling. The ABCA3 transporter, expressed in alveolar type II cells, imports phospholipids such as phosphatidylcholine into lamellar bodies, enabling the assembly and secretion of pulmonary surfactant to reduce surface tension in the lungs. Defects in ABCA3 cause neonatal respiratory distress by disrupting lamellar body biogenesis and surfactant function.^[54]^[5]

ABC Exporters

Bacterial Exporters

Bacterial ABC exporters are integral membrane proteins that utilize ATP hydrolysis to translocate diverse substrates, including lipids, antibiotics, and peptides, from the cytoplasm to the periplasm or extracellular space, thereby contributing to antibiotic resistance and bacterial virulence in prokaryotes. These transporters typically operate via an alternating access mechanism, transitioning from an inward-facing conformation to capture substrates to an outward-facing state for release. In Gram-negative bacteria, many form tripartite assemblies with periplasmic adaptor proteins and outer membrane channels to span the entire cell envelope. A quintessential example is MsbA in Escherichia coli, a homodimeric ABC exporter that acts as a dedicated lipid A flippase during lipopolysaccharide (LPS) biosynthesis. MsbA translocates the lipid A precursor from the inner to the outer leaflet of the cytoplasmic membrane, enabling its subsequent modification and transport to the outer membrane. This process is essential for forming a functional outer membrane barrier against environmental stresses. Temperature-sensitive mutations in msbA, such as the WD2 allele, impair lipid A flipping, leading to precursor accumulation in the inner membrane and hypersensitivity to detergents like SDS and bile salts, which mimic endotoxin exposure. MacB exemplifies ABC exporters involved in multidrug resistance, forming the core ATP-hydrolyzing subunit of the tripartite MacAB-TolC efflux pump in Gram-negative bacteria like E. coli. This assembly spans the inner membrane (MacB), periplasm (MacA adaptor), and outer membrane (TolC channel) to export macrolide antibiotics such as erythromycin, as well as other cytotoxic compounds. MacB's nucleotide-binding domains couple ATP binding and hydrolysis to drive conformational changes that propel substrates through the pump. Recent cryo-EM structures from the 2020s, including in situ assemblies of MacAB-TolC, have elucidated the dynamic fusion interfaces and peristaltic motion-like substrate threading, revealing how adaptor-mediated clustering enhances export efficiency under physiological conditions.^[55] The structure of Sav1866 from Staphylococcus aureus has served as a foundational model for understanding bacterial ABC exporter architecture and function. Resolved at 3.0 Å resolution in an outward-facing conformation bound to AMP-PNP, Sav1866 features six transmembrane helices per monomer forming a substrate-binding cavity that accommodates amphipathic molecules, including antimicrobial peptides. This homodimeric exporter uses ATP-driven dimerization of its nucleotide-binding domains to alternate access, facilitating the extrusion of drugs and host defense peptides to promote pathogen survival. Sav1866's topology, conserved across bacterial homologs, underscores its role in intrinsic resistance to cationic antimicrobial agents.

Eukaryotic Exporters

Eukaryotic ABC exporters play crucial roles in cellular detoxification and homeostasis by actively transporting a wide array of substrates, including xenobiotics, lipids, and metabolic byproducts, out of the cell or into specific organelles using ATP hydrolysis. These transporters, primarily from the ABCB, ABCC, and ABCG subfamilies, exhibit tissue-specific expression and contribute to protecting cells from toxic accumulation while maintaining essential physiological balances, such as lipid metabolism and drug efflux. Unlike prokaryotic counterparts, eukaryotic exporters often operate in compartmentalized environments, including plasma membranes, organelle boundaries, and barriers like the blood-brain interface, enhancing their role in multicellular organismal defense mechanisms.^[41] The ABCC subfamily, particularly ABCC1 (also known as MRP1), is a key player in exporting organic anions and conjugated metabolites, such as glutathione conjugates and leukotriene C4, alongside chemotherapeutic agents like vincristine and doxorubicin. Expressed at high levels in lung and kidney epithelial cells, ABCC1 facilitates the efflux of these compounds from the cytosol to the extracellular space, thereby preventing intracellular toxicity and supporting detoxification pathways in these barrier tissues. This activity is vital for protecting respiratory and renal cells from environmental toxins and oxidative stress products.^[56]^[57] ABCG2, commonly referred to as the breast cancer resistance protein (BCRP), exemplifies half-transporter exporters that dimerize to function, primarily effluxing hydrophobic drugs and metabolites such as mitoxantrone and sulfated estrogens. Highly expressed at the blood-brain barrier, ABCG2 restricts the entry of potentially neurotoxic substances into the central nervous system, maintaining brain homeostasis and contributing to drug resistance in cancers. Its role in limiting substrate penetration across endothelial barriers underscores its importance in systemic detoxification.^[58]^[59] In fungi, such as the yeast Saccharomyces cerevisiae, the ABC exporter Pdr5 serves as a polyspecific drug pump, expelling a broad spectrum of antifungal agents, cytotoxic compounds, and environmental toxins from the plasma membrane. As a major contributor to pleiotropic drug resistance, Pdr5 enables fungal cells to survive in hostile conditions, highlighting the conserved detoxification function of eukaryotic ABC exporters across kingdoms. Its broad substrate specificity mirrors that of mammalian counterparts, aiding in cellular survival and adaptation.^[60]^[61] Tissue-specific expression further refines these roles, as seen with ABCB11 (bile salt export pump, BSEP), which is predominantly localized in hepatocytes and exports bile acids from the liver into the bile canaliculi. This ATP-dependent transport is critical for bile flow and cholesterol homeostasis, preventing intrahepatic accumulation of bile salts that could lead to cholestasis. High hepatic expression of ABCB11 ensures efficient detoxification of bile acids, integrating ABC exporters into broader metabolic networks.^[62]^[63]

Notable Examples in Humans and Plants

In humans, the ABCB1 transporter, also known as P-glycoprotein (P-gp) or multidrug resistance protein 1 (MDR1), exemplifies a key eukaryotic exporter with a structure comprising two transmembrane domains (TMDs), each containing six transmembrane helices for a total of 12, connected to two nucleotide-binding domains (NBDs).^[64] This transporter exports over 100 diverse substrates, including chemotherapeutic agents like vinblastine, thereby contributing to multidrug resistance by effluxing xenobiotics from cells.^[65] Overexpression of ABCB1 is observed in many multidrug-resistant cancers, such as leukemia and lung cancer, where it limits the efficacy of treatments by pumping out drugs.^[66] In plants, the ABCB1 ortholog, known as PGP1, plays a crucial role in auxin efflux, facilitating polar auxin transport that directs root gravitropism and overall plant architecture by redistributing the hormone indole-3-acetic acid (IAA) in response to gravity cues.^[67] Similarly, plant ABCG transporters, such as ABCG11 and ABCG12 (also called WBC11 and CER5), are essential for exporting cuticular wax components, including very-long-chain fatty acids and alcohols, to form the hydrophobic cuticle layer that prevents water loss and pathogen entry on aerial surfaces.^[68] Additionally, plant ABCC1, ABCC2, and ABCC3 transporters contribute to heavy metal detoxification by sequestering cadmium-phytochelatin complexes into vacuoles, thereby enhancing tolerance to soil contaminants like cadmium in species such as Arabidopsis thaliana.^[69] Recent structural studies using cryo-electron microscopy (cryo-EM) have advanced understanding of ABCB1 function, revealing asymmetric conformational states during ATP hydrolysis when bound to inhibitors, which highlight distinct occluded intermediates in the transport cycle and inform strategies for targeting multidrug resistance. As of 2025, ongoing research includes high-resolution structures of ABCB1 in native lipid environments, providing insights into inhibitor binding and allosteric regulation.^[70]^[71]

Physiological Roles

Nutrient Uptake and Homeostasis

ABC transporters play crucial roles in nutrient uptake by facilitating the import of essential ions and metals, particularly in prokaryotes facing iron-limited environments. In bacteria such as Escherichia coli, the FepBDGC system exemplifies this function as an ABC importer for ferric enterobactin (Fe³⁺-Ent), a siderophore that chelates iron to enable its acquisition from the environment. The periplasmic binding protein FepB captures Fe³⁺-Ent and delivers it to the membrane-embedded permeases FepD and FepG, with FepC providing the ATP hydrolysis necessary for translocation across the inner membrane, thereby preventing iron deficiency and supporting cellular respiration and enzyme function.^[72] This high-affinity mechanism is vital in nutrient-poor settings, where ABC importers like FepBDGC consume a significant portion of cellular ATP to sustain nutrient acquisition.^[36] In eukaryotes, ABC transporters contribute to lipid homeostasis by regulating cholesterol efflux and high-density lipoprotein (HDL) formation. The ABCA1 transporter mediates the export of cholesterol and phospholipids from cells to apolipoprotein A-I (apoA-I), initiating nascent HDL particle assembly and maintaining systemic lipid balance. Defects in ABCA1, as seen in Tangier disease, result in impaired cholesterol efflux, leading to very low HDL levels and disrupted lipid homeostasis, underscoring ABCA1's essential role in preventing cellular lipid accumulation. ABC transporters also enable the uptake and distribution of vitamins critical for metabolism. In plants, ABCC subfamily members such as AtABCC1 and AtABCC4 transport folates across the tonoplast into vacuoles, ensuring folate availability for one-carbon metabolism and preventing deficiency in photosynthetic tissues. In humans, the ABCD4 transporter facilitates the export of vitamin B12 (cobalamin) from lysosomes to the cytosol, where it is converted to cofactors for DNA synthesis and energy production, thus supporting cellular homeostasis.^[73]^[74] Beyond importers, certain ABC exporters maintain membrane integrity and osmoregulation by preserving phospholipid asymmetry. The ABCB4 transporter (also known as MDR3) acts as a floppase in hepatocytes, translocating phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane, which stabilizes the bilayer against bile salts and supports bile composition homeostasis. This asymmetry is essential for osmotic balance and preventing membrane disruption in fluid-rich environments like the biliary tract.^[75]

Detoxification and Waste Export

ABC transporters play a crucial role in cellular detoxification by actively exporting xenobiotics and metabolic waste products, thereby protecting organisms from toxic accumulation. As ATP-dependent efflux pumps, these proteins utilize the energy from ATP hydrolysis to translocate substrates across membranes against concentration gradients, preventing damage from environmental pollutants and endogenous byproducts.^[76] In xenobiotic efflux, P-glycoprotein (P-gp, encoded by ABCB1) serves as a key exporter of environmental toxins, including the persistent pollutant DDT. Structural studies have revealed that DDT binds to the substrate-binding pocket within the transmembrane domains of P-gp, facilitating its ATP-driven extrusion from cells in various organisms, such as fish exposed to contaminated waters. This mechanism underscores P-gp's broad substrate specificity, which extends to numerous hydrophobic xenobiotics, contributing to the protein's protective function against chemical insults.^[77]^[78] For endogenous waste export, ABCC4 (also known as MRP4) efficiently transports cyclic nucleotides like cAMP and cGMP, as well as prostaglandins, out of cells to regulate intracellular signaling and prevent toxic buildup. Vesicle-based transport assays have demonstrated ABCC4's high affinity for these substrates, with Km values in the micromolar range, enabling precise control of second messenger levels in response to physiological demands. Mutations or inhibition of ABCC4 can lead to elevated intracellular concentrations, highlighting its essential role in maintaining cellular homeostasis.^[79]^[80] In plants, ABC transporters mediate stress responses by exporting the hormone abscisic acid (ABA) during drought, promoting stomatal closure to conserve water. Specifically, ABCG25 functions as an ABA exporter in Arabidopsis thaliana, localizing to the plasma membrane of vascular tissues and guard cells, where it facilitates ABA movement to apoplastic spaces for signaling. Cryo-EM structures of ABCG25 confirm its half-transporter architecture, with ABA binding sites that support efflux under water deficit conditions, enhancing drought tolerance.^[81]^[82] Bile acid export represents another vital detoxification pathway, primarily handled by ABCB11 (bile salt export pump, BSEP) in hepatocytes, which pumps monovalent bile acids into bile canaliculi for fecal elimination. Defects in ABCB11, such as missense mutations disrupting ATP binding, cause progressive familial intrahepatic cholestasis type 2 (PFIC2), leading to bile acid accumulation, liver damage, and jaundice in affected individuals. Clinical studies of PFIC2 patients reveal that over 100 ABCB11 variants correlate with impaired export efficiency, emphasizing BSEP's non-redundant role in hepatobiliary homeostasis.^[83]^[84] Evolutionary adaptations further illustrate the detoxification prowess of ABC transporters, with upregulation in contaminated environments conferring resistance. In insects, ABCG subfamily members, such as ABCG6 and ABCG9 in Plutella xylostella, are overexpressed in pesticide-resistant strains, actively effluxing insecticides like chlorantraniliprole and reducing intracellular toxicity. Genomic analyses of resistant populations show that ABCG gene amplification enhances survival in agrochemical-exposed habitats, demonstrating natural selection for robust export mechanisms.^[85]^[86]

Developmental and Signaling Functions

ABC transporters exhibit diverse non-canonical functions beyond solute transport, particularly in cellular signaling and developmental processes, where certain subfamilies lacking transmembrane domains act as regulatory factors in translation and morphogenesis.^[87] ABCE1, a soluble ABC transporter devoid of transmembrane domains, plays a critical role in ribosome biogenesis and the initiation of protein translation in eukaryotes. It facilitates the disassembly of post-termination ribosomal complexes and promotes the formation of the 48S pre-initiation complex during translation start, ensuring efficient recycling of ribosomal subunits for subsequent rounds of protein synthesis. Depletion of ABCE1 impairs S-phase progression in human cells by disrupting translation fidelity and ribosome assembly, highlighting its essential function in cell proliferation and development.^[88]^[89]^[87] Members of the ABCF subfamily, also lacking transmembrane domains, contribute to bacterial antibiotic resistance through ribosome protection mechanisms that indirectly safeguard mRNA translation. These proteins bind to the ribosome's peptidyl transferase center, displacing antibiotics that target the 50S subunit and thereby preventing inhibition of protein synthesis. For instance, ABCF-mediated resistance in pathogens like Staphylococcus aureus modulates global translation responses to antimicrobial stress, influencing bacterial survival and adaptation during infection. This protective role extends to non-resistance functions in translation regulation, underscoring ABCF's involvement in cellular signaling under environmental pressures.^[90]^[91]^[92] In plants, ABCB1 and ABCB19 transporters direct auxin morphogen gradients essential for embryogenesis and organ development. These efflux carriers localize to suspensor and pro-embryonic cells, establishing polarized auxin flow that patterns the embryonic axis and promotes apical-basal differentiation. Mutations in ABCB19 disrupt post-embryonic auxin distribution, leading to defects in tropisms and vascular development, while synergistic action with ABCB1 ensures robust morphogen signaling for proper seedling establishment.^[93]^[94]^[95] ABCA4, known as the rim protein in photoreceptor outer segments, exports retinal derivatives to maintain the visual cycle and support eye development. This importer flips N-retinylidene-phosphatidylethanolamine from the disc lumen to the cytoplasm, preventing accumulation of toxic bisretinoids that could impair retinal maturation. Loss-of-function mutations in ABCA4 cause Stargardt disease, a juvenile macular dystrophy that disrupts photoreceptor function and leads to progressive vision loss during critical developmental windows.^[96]^[97]^[98] ABCC11 influences immune and social signaling by exporting axillary odorants, including potential pheromones, that modulate human interpersonal behavior. A functional ABCC11 allele is required for the biochemical formation of these odor compounds, with variants leading to reduced odor production and altered social perceptions such as attractiveness and group cohesion. This export function links olfaction to behavioral signaling, affecting mate selection and emotional contagion in social contexts.^[99]^[100]

Roles in Disease and Drug Resistance

Multidrug Resistance in Cancer and Infections

ABC transporters, particularly exporters, play a central role in multidrug resistance (MDR) by actively pumping chemotherapeutic agents and antibiotics out of cells, thereby reducing their intracellular concentrations and diminishing therapeutic efficacy.^[101] In cancer, overexpression of these transporters in tumor cells confers resistance to a broad spectrum of drugs, while in infections, bacterial ABC transporters contribute to antibiotic evasion, complicating treatment of multidrug-resistant pathogens.^[102] This phenomenon is a major barrier to successful therapy, as it allows cancer cells and bacteria to survive exposure to otherwise lethal doses. In tumors, P-glycoprotein (P-gp, encoded by ABCB1) is a key mediator of MDR, effluxing diverse anticancer drugs such as anthracyclines, taxanes, and vinca alkaloids, which reduces intracellular drug levels by 10- to 100-fold.^[101] This efflux activity limits drug accumulation below cytotoxic thresholds, promoting tumor survival and relapse. Overexpression of P-gp has been documented across various malignancies, including colorectal, breast, and ovarian cancers, where it correlates with poor prognosis and treatment failure.^[102] Mechanisms driving ABC transporter overexpression in cancer include increased transcription regulated by nuclear factor kappa B (NF-κB), which activates ABCB1 promoters in response to cellular stress or inflammation.^[103] Additionally, gene amplification of ABCB1 leads to elevated copy numbers and sustained high expression, further enhancing efflux capacity in resistant cell lines.^[66] Clinically, ABC-mediated resistance profoundly impacts acute myeloid leukemia (AML) treatment, where a substantial proportion of patients exhibit transporter activity contributing to daunorubicin resistance, reducing response rates and overall survival.^[104] This high prevalence underscores the role of ABC transporters like ABCB1 and ABCG2 in limiting anthracycline efficacy, often resulting in refractory disease. In bacterial infections, variants of the ABC transporter MsbA in Gram-negative pathogens like Escherichia coli confer resistance to polymyxins by altering lipopolysaccharide transport and outer membrane integrity, thereby reducing antibiotic penetration and lethality.^[105] MsbA mutations disrupt lipid A flipping, which indirectly bolsters membrane stability against polymyxin disruption.^[106] Recent studies using single-cell RNA sequencing in the 2020s have revealed elevated ABCG2 expression specifically in cancer stem cells across multiple tumor types, including leukemia and solid tumors, highlighting its role in maintaining stemness and driving persistent MDR within heterogeneous tumor populations.^[107] These findings emphasize ABCG2 as a therapeutic target in stem cell-enriched niches resistant to conventional chemotherapy.^[108]

Genetic Disorders Linked to ABC Dysfunctions

Mutations in genes encoding ATP-binding cassette (ABC) transporters can lead to a variety of inherited monogenic disorders by disrupting the transport of essential substrates across cellular membranes, thereby affecting physiological homeostasis such as ion balance, lipid metabolism, and detoxification processes.^[109] These dysfunctions often manifest as recessive or X-linked conditions with varying prevalence, highlighting the critical role of ABC proteins in human health.^[110] Cystic fibrosis (CF), caused by mutations in the CFTR gene (also known as ABCC7), is the most common lethal autosomal recessive disorder among individuals of European descent, affecting approximately 100,000 people worldwide.^[111] The most prevalent mutation, ΔF508 (p.Phe508del), accounts for about two-thirds of CFTR alleles in affected patients and results in protein misfolding, leading to defective chloride ion transport across epithelial membranes and subsequent mucus accumulation in organs like the lungs and pancreas.^[112] This impairment disrupts airway surface liquid homeostasis, predisposing individuals to chronic infections and progressive lung damage.^[109] Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by conjugated hyperbilirubinemia due to mutations in the ABCC2 gene, which encodes the multidrug resistance-associated protein 2 (MRP2).^[113] These mutations impair the export of conjugated bilirubin from hepatocytes into bile, resulting in its accumulation in the liver and causing benign jaundice without significant liver dysfunction.^[114] The condition is typically asymptomatic beyond intermittent jaundice episodes, often triggered by stress or infections.^[115] X-linked adrenoleukodystrophy (X-ALD) arises from mutations in the ABCD1 gene, which encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal half-transporter essential for importing very long-chain fatty acids (VLCFAs) into peroxisomes for β-oxidation.^[116] Defective ABCD1 function leads to VLCFA accumulation in tissues, particularly affecting the central nervous system and adrenal glands, resulting in progressive neurological deterioration, adrenal insufficiency, and demyelination in about 30-40% of male patients.^[117] The disorder exhibits variable phenotypes, from childhood cerebral forms to adult-onset adrenomyeloneuropathy.^[118] Mutations in the ABCA4 gene cause Stargardt disease (STGD1), the most common inherited macular dystrophy, with a prevalence of approximately 1 in 8,000 to 10,000 individuals.^[119] ABCA4 encodes a retinal-specific ABC transporter that flips N-retinylidene-phosphatidylethanolamine from the luminal to the cytoplasmic side of photoreceptor outer segment discs, facilitating the clearance of toxic visual cycle byproducts; pathogenic variants lead to lipofuscin accumulation in the retinal pigment epithelium, causing progressive central vision loss typically in adolescence or early adulthood.^[120] Over 1,000 ABCA4 mutations have been identified, contributing to a spectrum of retinopathies including cone-rod dystrophy.^[121] Tangier disease, caused by mutations in the ABCA1 gene, is a rare autosomal recessive disorder characterized by very low levels of high-density lipoprotein (HDL) cholesterol, accumulation of cholesterol esters in macrophages, and increased risk of premature atherosclerosis and neuropathy due to impaired cholesterol efflux from cells to apolipoprotein A-I.^[3] Therapeutic advancements for ABC-related disorders include the 2012 FDA approval of ivacaftor (Kalydeco), the first CFTR potentiator for cystic fibrosis patients with specific gating mutations like G551D, which enhances channel opening and improves lung function in responsive individuals. Subsequent triple combination therapies, such as elexacaftor/tezacaftor/ivacaftor (Trikafta, approved 2019) and vanzacaftor/tezacaftor/ivacaftor (Alyftrek, approved 2024), target the common ΔF508 mutation and are eligible for approximately 90% of CF patients aged 6 years and older, significantly improving lung function, reducing exacerbations, and enhancing quality of life.^[122]^[123]^[124] This milestone has paved the way for modulator therapies targeting ΔF508 misfolding, with ongoing research into mRNA-based and gene therapies to address remaining genotypes.^[125]

Strategies for Overcoming Resistance

First-generation inhibitors of ABC transporters, such as verapamil, were among the earliest agents identified to reverse multidrug resistance by competitively blocking efflux pumps like ABCB1 (P-glycoprotein).^[126] These compounds, originally developed as calcium channel blockers, demonstrated the ability to sensitize resistant cancer cells to chemotherapeutic drugs like vincristine and doxorubicin in preclinical models. However, their clinical utility was severely limited by high toxicity arising from off-target effects, particularly Ca2+ channel blockade, which led to cardiovascular side effects and required doses far exceeding those needed for transporter inhibition.^[127] To address the limitations of first- and second-generation inhibitors, third-generation agents like tariquidar were designed for greater specificity toward ABCB1 with minimal impact on other transporters or physiological processes.^[128] Tariquidar exhibits potent inhibition of ABCB1-mediated efflux, achieving an IC50 of approximately 10 nM in cell-based assays, allowing effective reversal of resistance at low concentrations without the broad pharmacological interactions seen in earlier compounds.^[129] Despite promising preclinical results, including enhanced brain penetration of substrates in animal models, tariquidar has not yet progressed to widespread clinical approval due to challenges in demonstrating consistent therapeutic benefits in human trials.^[130] Genetic approaches offer an alternative to pharmacological inhibition by directly targeting ABC transporter expression. For instance, CRISPR-Cas9-mediated knockout of ABCG2 in preclinical cancer cell models, such as non-small cell lung carcinoma lines, has been shown to restore sensitivity to substrates like topotecan by eliminating efflux activity.^[131] Similarly, siRNA-mediated knockdown of ABCG2 in glioblastoma models reduces transporter levels by up to 80%, potentiating the intracellular accumulation of chemotherapeutic agents and overcoming resistance in vitro and in xenograft studies.^[132] These methods provide precise control but face hurdles in delivery and off-target editing risks for in vivo applications.^[133] Combination therapies integrating ABC inhibitors with standard chemotherapeutics represent a practical strategy to enhance treatment efficacy against resistance mediated by transporters like ABCB1 and ABCG2. In preclinical studies, co-administration of inhibitors such as elacridar with drugs like paclitaxel has increased tumor cell killing by 2- to 5-fold in resistant ovarian and breast cancer models, as measured by reduced IC50 values and improved apoptosis rates.^[128] This synergy arises from elevated intracellular drug levels, with clinical trials exploring similar pairings showing up to 3-fold improvements in response rates for refractory leukemias.^[134] Ongoing research emphasizes optimizing dosing to minimize toxicity while maximizing penetration in sanctuary sites like the brain.^[135]

Classification and Subfamilies

Evolutionary and Structural Classification

ABC transporters are phylogenetically classified into seven major subfamilies, designated A through G, primarily based on the architectural topology of their transmembrane domains (TMDs) and the sequence relatedness of their nucleotide-binding domains (NBDs). This classification reflects shared evolutionary histories and functional divergences across prokaryotes and eukaryotes, with subfamily assignments determined through comprehensive sequence alignments and phylogenetic analyses. In humans, for instance, this grouping encompasses 48 ABC genes, but the subfamilies are conserved across diverse organisms, highlighting their ancient origins.^[136] Structurally, ABC transporters exhibit two primary architectures: full transporters, which integrate four core domains—two TMDs and two NBDs—into a single polypeptide chain, and half transporters, comprising one TMD fused to one NBD, which typically dimerize to form functional units. Full transporters often mediate unidirectional export or import across membranes, while half transporters, upon dimerization, achieve similar capabilities but allow for greater modularity in substrate specificity. These domain organizations are conserved, with TMDs forming substrate-binding pathways and NBDs powering transport via ATP hydrolysis. Brief domain structures underscore this duality, where TMDs span the membrane with 5-6 helices each, interfacing with NBDs through intracellular loops.^[137] The evolutionary roots of ABC transporters trace to ancient prokaryotic importers, emerging around 3.5 billion years ago through gene duplication of primordial ATP-binding modules in the last universal common ancestor. This duplication event facilitated the expansion from simple import systems in early bacteria to diverse exporters in eukaryotes, driven by selective pressures for nutrient acquisition and toxin efflux. Subsequent divergences produced specialized lineages, with prokaryotic importers predominating in bacterial genomes and eukaryotic exporters adapting to complex cellular environments.^[138]^[139] Certain subfamilies, notably ABCE and ABCF, represent non-transporter variants that lack TMDs entirely, consisting solely of fused NBDs adapted for cytosolic functions such as ribosome assembly, mRNA translation initiation, and quality control. These soluble proteins diverged early from membrane-bound ancestors, repurposing ATP-binding motifs for regulatory roles independent of translocation. The Transporter Classification Database (TCDB) catalogs the entire ABC superfamily under identifier 3.A.1, documenting over 10,000 non-redundant sequences that span importers, exporters, and these atypical members across all domains of life.^[140]^[141]

Mammalian Subfamilies

In humans, the ABC transporter superfamily encompasses 48 genes organized into seven subfamilies (ABCA through ABCG), with functions ranging from lipid and ion transport to roles in protein synthesis regulation.^[142] These subfamilies exhibit distinct domain architectures and subcellular localizations, reflecting their specialized physiological roles.^[136] While most subfamilies encode full or half-transporters embedded in membranes, ABCE and ABCF members are soluble and non-transporting.^[143] The ABCA subfamily includes 12 genes and is characterized by large full transporters (typically ~2,500 amino acids) dedicated to lipid translocation across membranes. These proteins primarily handle amphipathic lipids, such as phospholipids, cholesterol, and retinoids, contributing to lipid homeostasis in tissues like the lung, eye, and brain. A key example is ABCA1, which promotes cholesterol efflux from macrophages to apolipoprotein A-I, forming high-density lipoprotein particles essential for reverse cholesterol transport; mutations in ABCA1 cause Tangier disease, marked by low HDL levels and atherosclerosis risk.^[136] Another notable member, ABCA4, transports retinoids in photoreceptor cells to prevent lipofuscin accumulation, with defects leading to Stargardt disease and retinal degeneration.^[144] The ABCB subfamily consists of 11 genes, encoding both full and half-transporters localized to the plasma membrane, mitochondria, or endoplasmic reticulum, with diverse substrates including peptides, drugs, and bile acids. ABCB1, also known as P-glycoprotein (P-gp), is a prototypical full transporter that effluxes a broad range of xenobiotics and chemotherapeutic agents from cells, conferring multidrug resistance in cancer.^[136] In the ER, ABCB4 functions as a phospholipid flippase, translocating phosphatidylcholine into bile canaliculi to protect against cholesterol gallstone formation; its deficiency results in progressive familial intrahepatic cholestasis type 3.^[142] Mitochondrial members like ABCB7 and ABCB10 support iron homeostasis by exporting iron-sulfur clusters for heme and Fe/S cluster biogenesis.^[5] Comprising 12 genes, the ABCC subfamily (also called the multidrug resistance-associated protein or MRP family) features full transporters that export organic anions, conjugates, and heavy metals, often with an additional N-terminal transmembrane domain. These proteins are involved in detoxification and ion transport, with several contributing to drug resistance. ABCC7, or cystic fibrosis transmembrane conductance regulator (CFTR), uniquely acts as an ATP-gated chloride channel rather than a typical exporter, regulating ion and fluid secretion in epithelial tissues; mutations cause cystic fibrosis, the most common lethal genetic disorder in Caucasians.^[136] ABCC1 (MRP1) effluxes glutathione conjugates and anticancer drugs like vincristine, playing a role in cellular protection against oxidative stress and chemotherapy resistance.^[142] The ABCD subfamily has 4 genes, all half-transporters targeted to peroxisomal membranes, where they import very long-chain fatty acids and plasmalogens for beta-oxidation. ABCD1 is critical for transporting acyl-CoA esters into peroxisomes; its dysfunction due to mutations leads to X-linked adrenoleukodystrophy, a demyelinating disorder affecting the nervous system and adrenals.^[136] The other members (ABCD2–4) share similar functions but with varying substrate specificities, such as ABCD3 transporting branched-chain fatty acids.^[142] Unlike other subfamilies, ABCE and ABCF do not form transmembrane domains and function in the cytosol as regulators of translation. The ABCE subfamily has 1 gene (ABCE1), which associates with the ribosome for disassembly and recycling after translation termination, essential for protein synthesis and influencing antiviral responses via interferon pathways.^[143] The ABCF subfamily includes 3 genes (ABCF1–3), which bind the ribosome to modulate elongation and antibiotic resistance.^[142] The ABCG subfamily contains 5 genes, all reverse-oriented half-transporters that dimerize or oligomerize to form functional units, primarily exporting sterols, lipids, and xenobiotics from the plasma membrane. ABCG2 (breast cancer resistance protein) transports heme, porphyrins, and chemotherapeutic drugs like mitoxantrone, contributing to the blood-brain and blood-testis barriers as well as multidrug resistance in stem cells and tumors.^[136] ABCG5 and ABCG8 form a heterodimer in enterocytes and hepatocytes to limit dietary sterol absorption, with biallelic mutations causing sitosterolemia, characterized by xanthomas and premature atherosclerosis due to plant sterol accumulation.^[142]

Non-Mammalian Subfamilies

In bacteria, ABC transporters constitute a significant portion of the membrane proteome, with approximately 50 genes encoding these proteins in many species, the majority functioning as importers for essential nutrients and ions.^[13] These importers typically consist of a substrate-binding protein in the periplasm, coupled to transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) that harness ATP hydrolysis to drive uptake. For instance, systems like the maltose importer in Escherichia coli exemplify this importer dominance, facilitating the transport of carbohydrates, amino acids, peptides, vitamins, and metal ions critical for bacterial survival and virulence.^[13] While exporters exist, such as those for antimicrobial peptides or toxins, they are less prevalent compared to importers in prokaryotes.^[145] In plants, the ABC transporter family is notably expanded, comprising over 120 genes across species like Arabidopsis thaliana, classified into eight subfamilies (A through G and I).^[146] The ABCG subfamily plays a key role in pathogen defense by exporting antimicrobial compounds, such as cuticular waxes and secondary metabolites that deter fungal and bacterial infections at the cell surface.^[147] Meanwhile, the ABCC subfamily is prominent in vacuolar sequestration, transporting heavy metals, glutathione conjugates, and xenobiotics into vacuoles for detoxification and homeostasis, thereby protecting cellular compartments from toxicity.^[146] This expansion, particularly in ABCB, ABCC, and ABCG subfamilies, reflects adaptations to terrestrial environments, including interactions with soil microbes and pollutants.^[147] Fungal ABC transporters are predominantly exporters, with the pleiotropic drug resistance (PDR) subfamily—analogous to ABCG—being the largest and most studied for antifungal resistance.^[148] In pathogenic yeasts like Candida albicans, the PDR member Cdr1 exports azole antifungals, steroids, and other xenobiotics, contributing to multidrug resistance in clinical isolates.^[148] This subfamily, comprising up to nine members in some fungi, often features an inverted topology with NBDs preceding TMDs, enabling efficient efflux across the plasma membrane.^[149] Other PDR transporters, such as Pdr5 in Saccharomyces cerevisiae, similarly handle environmental toxins, underscoring their role in fungal adaptation to hostile niches.^[150] In protozoan parasites, ABC transporters mediate drug resistance, with notable examples in malaria-causing Plasmodium falciparum. The PfMDR1 protein, a member of the ABCB subfamily, localizes to the digestive vacuole membrane and modulates chloroquine accumulation, thereby conferring resistance by effluxing the antimalarial from the parasite cytosol.^[151] Polymorphisms in pfmdr1 alter substrate specificity, impacting responses to multiple drugs like quinine and mefloquine.^[152] Similar ABC transporters in other protozoa, such as trypanosomes, export trypanocidal drugs, highlighting their conserved yet adapted roles in parasite survival against host defenses and chemotherapeutics.^[153] Across kingdoms, ABC transporters exhibit high conservation in the core NBD motifs, including Walker A/B sequences and the ABC signature, which are nearly identical for ATP binding and hydrolysis, ensuring a universal transport mechanism.^[4] In contrast, TMDs show greater divergence, tailored to kingdom-specific substrates like bacterial ions, plant xenobiotics, or protozoan drugs, reflecting evolutionary adaptations while maintaining the fundamental ATP-driven conformational changes.^[137] This structural modularity allows functional specialization without altering the energetic core.^[154]

Research Methods

Structural and Biophysical Techniques

Structural and biophysical techniques have been essential in elucidating the architecture and conformational dynamics of ABC transporters, which are challenging due to their membrane-embedded nature. Early efforts focused on X-ray crystallography of isolated nucleotide-binding domains (NBDs), providing foundational insights into ATP-binding motifs. The first high-resolution structure of an NBD was determined for HisP from Salmonella typhimurium in 1998 at 1.5 Å resolution, revealing the characteristic L-shaped fold with RecA-like and helical subdomains, including key elements like the Walker A and B motifs and the ABC signature sequence. Subsequent crystallographic studies in the late 1990s and early 2000s extended this to other NBDs, such as MalK from Escherichia coli, confirming conserved dimerization interfaces that sandwich two ATP molecules head-to-tail. A landmark advance came in 2006 with the 3.0 Å crystal structure of the full-length bacterial ABC exporter Sav1866 from Staphylococcus aureus, captured in an outward-facing conformation with nucleotide analogs, demonstrating how NBD dimerization couples to transmembrane domain (TMD) rearrangement for substrate export. These X-ray structures established the alternating access model, where NBD closure drives TMD opening to the extracellular side, though challenges persisted in stabilizing full eukaryotic transporters in detergents. Cryo-electron microscopy (cryo-EM) has become the preferred method for resolving near-native structures of membrane-embedded ABC transporters, overcoming limitations of crystallization by imaging proteins in lipid nanodiscs or amphipols. Since 2017, cryo-EM has yielded multiple structures of human P-glycoprotein (P-gp, ABCB1) at resolutions of 3-4 Å, revealing conformational states during the transport cycle. For instance, the 3.4 Å structure of human P-gp in the ATP-bound outward-facing state, determined in 2018, highlighted the inward-to-outward transition with splayed TMDs and closed NBDs, stabilized by AMP-PNP.^[155] Higher-resolution cryo-EM maps (down to ~2.5 Å as of 2024) have since captured substrate-bound and inhibited forms, showing how central cavities accommodate diverse ligands and how lipid interactions modulate gating helices.^[156] Recent advances as of 2025 include structures of novel ABC transporters like the Gram-positive type VII YtrBCD and YtrEF at resolutions better than 3 Å, providing insights into substrate specificity in bacterial systems.^[157] This technique's ability to handle heterogeneous samples has been particularly valuable for mammalian ABCs, providing dynamic snapshots that X-ray methods struggled to achieve. Nuclear magnetic resonance (NMR) spectroscopy complements crystallography and cryo-EM by probing solution-state dynamics, especially NBD dimerization and nucleotide interactions in detergent micelles or liposomes. Solution NMR studies of isolated NBDs, such as those from the multidrug exporter LmrA in Lactococcus lactis, have revealed residue-specific chemical shift perturbations upon ATP binding, indicating subdomain rotations that facilitate dimer interface formation.^[158] A seminal NMR investigation of the heterodimeric NBDs from human MRP1 (ABCC1) in 2006 demonstrated transient dimerization in solution, with intermolecular NOEs confirming head-to-tail ATP sandwiching and highlighting asymmetry in eukaryotic transporters.^[159] More recent solid-state NMR on full-length transporters like BmrA has extended this to membrane environments, tracking asymmetric ATP hydrolysis and NBD separation post-dimerization at atomic resolution.^[160] These approaches underscore the transient nature of NBD contacts, essential for the power stroke in transport. Computational modeling, particularly with deep learning-based tools like AlphaFold, has accelerated structure prediction for understudied ABC subfamilies lacking experimental data. Released in 2021, AlphaFold2 accurately predicted TMD helices and NBD folds for human ABC transporters, achieving median backbone RMSDs below 2 Å for crystallized examples and enabling homology modeling of uncrystallized ones like certain ABCC exporters.^[161] For instance, AlphaFold predictions of ABCG2 (BCRP) in 2021 revealed a dimeric architecture with intertwined TMDs, later validated by cryo-EM, and facilitated docking studies of inhibitors in novel subfamilies. The 2024 release of AlphaFold3 has further improved predictions for multi-subunit ABC complexes, incorporating ligand interactions and enabling more accurate modeling of eukaryotic heterodimers like ABCA1-ABCG1.^[162] These models highlight conserved domain interactions, such as coupling helices linking TMDs to NBDs, aiding design of variants for functional studies. As of 2025, machine learning approaches are also being applied to predict efflux and inhibition profiles for drug discovery.^[163] Despite these advances, structural studies of ABC transporters face limitations from detergent-solubilized preparations, which often disrupt native lipid environments and stabilize non-physiological conformations. Detergents like DDM can cause over-delipidation, leading to destabilized TMDs and altered NBD-TMD coupling, as evidenced by wider inward-facing states compared to lipid-embedded cryo-EM structures.^[164] Efforts to mitigate this include styrene-maleic acid copolymers for native nanodiscs, but detergent artifacts remain a caveat in interpreting dynamics for drug design.^[165]

Functional Assays in Membranes and Cells

Functional assays in membranes and cells are essential for evaluating the transport activity, kinetics, and modulation of ABC transporters, providing direct measurements of substrate movement and energy coupling in controlled environments. These methods complement structural studies by quantifying functional parameters such as uptake rates, efflux efficiency, and ATP hydrolysis, often using reconstituted systems or engineered cell lines to isolate specific transporter activities. By focusing on in vitro and cellular contexts, these assays enable the identification of substrates, inhibitors, and mechanistic insights without relying on whole-organism complexity. Vesicle-based assays utilize reconstituted proteoliposomes to assess ABC transporter function in a defined lipid environment, allowing precise measurement of substrate translocation driven by ATP. Purified ABC transporters, such as ABCA1 or ABCB4, are incorporated into large unilamellar vesicles (typically 100–200 nm) via detergent-mediated reconstitution, followed by removal of the detergent using dialysis or Bio-Beads to form sealed proteoliposomes with controlled orientation. Transport activity is then measured by monitoring the uptake or efflux of radiolabeled or fluorescent substrates; for example, ABCG5-ABCG8 facilitates the ATP-dependent uptake of [³H]cholesterol into proteoliposomes, achieving approximately 10% accumulation in a phosphatidylcholine:phosphatidylethanolamine:phosphatidylserine:phosphatidylinositol:sphingomyelin:cardiolipin mixture. Similarly, fluorescent analogs like NBD-PC (nitrobenzoxadiazole-phosphatidylcholine) are used to quantify translocation, with ABCA1 showing about 8.5% uptake in phosphatidylglycerol liposomes, detected via dithionite quenching assays that differentiate outer- versus inner-leaflet fluorescence. These assays reveal transport rates and directionality, with efficiencies varying by lipid composition and transporter type, such as ~6.5% NBD-PC efflux for ABCB4 in liver-like lipids. ATPase activity assays provide a direct readout of the energy consumption coupled to transport, commonly employing an NADH-coupled enzymatic system to monitor ATP hydrolysis in real time. In this method, purified or membrane-embedded ABC transporters hydrolyze ATP, producing ADP that is converted back to ATP by pyruvate kinase, while lactate dehydrogenase oxidizes NADH to NAD⁺, causing a measurable decrease in absorbance at 340 nm proportional to hydrolysis rate. For P-glycoprotein (ABCB1), basal ATPase activity is low, but substrate stimulation increases the turnover number to approximately 3.5–10 s⁻¹, as observed with vinblastine, reflecting 2–3 ATP molecules hydrolyzed per transport cycle under physiological conditions. This assay is widely used to screen modulators, where inhibitors like verapamil reduce stimulated rates, confirming allosteric coupling between substrate binding and nucleotide hydrolysis sites. In cell lines overexpressing ABC transporters, cytotoxicity and fluorescence-based assays evaluate efflux-mediated resistance and accumulation dynamics. The MTT assay measures cell viability via mitochondrial reduction of MTT to formazan, quantifying resistance by increased IC₅₀ values for toxic substrates in transporter-expressing cells; for instance, doxorubicin exposure (0–100 µM) in P-gp-overexpressing Caco-2 cells shows reduced cytotoxicity due to enhanced efflux, with EC₅₀ shifts indicating modulator efficacy. Flow cytometry with fluorescent dyes like calcein-AM assesses real-time efflux, where the non-fluorescent ester enters cells, is hydrolyzed to fluorescent calcein by esterases, and is pumped out by transporters such as P-gp or MRP1 (ABCC1), resulting in low intracellular fluorescence; inhibitors increase accumulation, detectable as heightened mean fluorescence intensity in lines like Caco-2 or lymphocytes. This method supports high-throughput screening, with calcein-AM specificity for multiple ABCs allowing parallel evaluation of inhibitors. For ion-conducting ABC transporters like CFTR (ABCC7), patch-clamp electrophysiology records chloride currents to probe channel gating and conductance. In the excised inside-out configuration, patches from heterologous cells (e.g., CHO expressing CFTR) are voltage-clamped, with intracellular ATP (1 mM) and PKA (75–200 nM) activating the channel, yielding single-channel currents of 6–10 pS under symmetric 150 mM Cl⁻ conditions and a linear current-voltage relationship. Wild-type CFTR exhibits open probabilities (P₀) up to 0.5, while mutants like G551D show reduced P₀ (~0.025), highlighting regulatory defects; this technique elucidates ATP-dependent gating cycles unique to CFTR among ABCs. High-throughput adaptations leverage heterologous expression systems like yeast or Xenopus oocytes for inhibitor screening, enabling scalable assessment of transport modulation. In yeast (Saccharomyces cerevisiae), human ABCs such as P-gp are expressed, and efflux is screened via growth restoration on toxic substrates or fluorescence assays, identifying inhibitors that sensitize cells to drugs like doxorubicin. Xenopus oocytes, injected with cRNA for ABC expression, support uptake assays with radiolabeled substrates (e.g., [³H]-ABA for plant ABCs), measuring accumulation rates to screen libraries, with advantages in low endogenous transport noise and suitability for electrophysiology. These platforms facilitate rapid testing of compound libraries, prioritizing hits for follow-up in mammalian cells.

In Vivo and Genetic Approaches

In vivo and genetic approaches have been instrumental in elucidating the physiological roles of ABC transporters by manipulating their expression in whole organisms or through large-scale genetic screens, providing insights into their contributions to disease and drug response. These methods leverage model organisms like mice, bacteria, and nematodes to assess context-dependent functions, such as lipid homeostasis and pathogen virulence, which cannot be fully captured in isolated systems. By generating targeted mutations or using genome-editing tools, researchers can observe phenotypic outcomes that link ABC transporter activity to broader biological processes. Knockout mouse models have been pivotal in studying the role of ABCA1 in cardiovascular disease. Abca1-/- mice exhibit profound reductions in high-density lipoprotein (HDL) cholesterol levels and develop accelerated atherosclerosis when crossed with apolipoprotein E-deficient (ApoE-/-) backgrounds, demonstrating ABCA1's essential function in reverse cholesterol transport and protection against plaque formation. These models reveal that macrophage-specific ABCA1 deficiency exacerbates foam cell accumulation and lesion progression in atherogenic environments, highlighting its therapeutic potential in lipid disorders.^[166]^[167] In bacterial systems, genetic disruption of ABC transporters underscores their indispensability for viability and pathogenesis. Deletion of the msbA gene, which encodes an ABC transporter responsible for flipping lipid A precursors across the inner membrane, is lethal in Salmonella enterica serovar Typhimurium due to defective lipopolysaccharide (LPS) assembly and outer membrane integrity. To investigate virulence, researchers employ plasmid-complemented ΔmsbA strains or suppressor mutants, revealing that restored MsbA function is required for efficient bacterial survival in host tissues and systemic infection, as compromised lipid A transport attenuates invasiveness in murine models.^[168] CRISPR-based genome-wide screens have identified ABC transporter dependencies in cancer, particularly in chemoresistance mechanisms. In human cancer cell lines, CRISPR knockout screens targeting ABC genes, such as ABCB1 and ABCC1, demonstrate that their inactivation sensitizes cells to chemotherapeutic agents like doxorubicin and paclitaxel by impairing drug efflux, thereby revealing convergent genetic vulnerabilities across tumor types. These screens, conducted under drug selection pressures, quantify essentiality scores showing that ABC transporters promote survival in multidrug-resistant contexts, guiding precision oncology strategies.^[169]^[170] Reporter assays in model organisms enable visualization of ABC transporter localization and dynamics in vivo. In Caenorhabditis elegans, GFP-tagged ABC transporters, such as HMT-1 (ABCB6 ortholog), localize primarily to the apical membrane of intestinal cells and endosomal compartments, facilitating heavy metal detoxification and ion homeostasis. These fluorescent fusions, expressed under tissue-specific promoters, track real-time trafficking during stress responses, confirming that N-terminal extensions are critical for proper apical targeting and physiological function in the gut.^[171]^[172] Pharmacogenetic studies, including genome-wide association studies (GWAS), link ABC polymorphisms to inter-individual variability in drug response. The ABCB1 3435C>T variant (rs1045642), which alters P-glycoprotein expression and function, has been associated with altered pharmacokinetics and efficacy of substrates like antiepileptics and antiretrovirals; for instance, the T allele correlates with reduced drug clearance and higher resistance risk in epilepsy cohorts. GWAS in diverse populations confirm this variant's role in modulating virologic response to efavirenz-containing regimens, influencing steady-state plasma levels and treatment outcomes in HIV patients.^[173]^[174]

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Nov 1, 2020 · ABC-F proteins generally function as translation factors that modulate the conformation of the peptidyl transferase center upon binding to the ribosomal tRNA ...
[91]
Auxin transport routes in plant development
Aug 15, 2009 · ABCB1 is localized to all suspensor cells (see Glossary, Box 1) and pro-embryonal cells,and ABCB19 localization is restricted to the suspensor- ...
[92]
The ATP-Binding Cassette Transporter ABCB19 Regulates ...
The phytohormone auxin plays a critical role in plant development, including embryogenesis, organogenesis, tropism, apical dominance and in cell growth, ...
[93]
ABCB1 and ABCB19 auxin transporters have synergistic effects on ...
Jan 27, 2015 · In conclusion, we provide evidence that auxin transport plays a significant role both in early and late stamen development: ABCB1 plays a major ...Missing: embryogenesis | Show results with:embryogenesis
[94]
The Role of the Photoreceptor ABC Transporter ABCA4 in Lipid ...
ABCA4 is a member of the ABCA subfamily of ATP binding cassette (ABC) transporters that is expressed in rod and cone photoreceptors of the vertebrate retina.
[95]
Structure and function of ABCA4 and its role in the visual cycle and ...
Dec 23, 2021 · Loss-of-function mutations in the gene encoding ABCA4 cause autosomal recessive Stargardt macular degeneration, also known as Stargardt disease ...
[96]
ATP-binding cassette transporter ABCA4 and chemical ... - PNAS
ABCA4 is an ATP-binding cassette transporter encoded by the gene responsible for Stargardt macular degeneration, an inherited retinopathy associated with ...Results · Abca4 Transports Both The... · Materials And Methods
[97]
A functional ABCC11 allele is essential in the biochemical ... - PubMed
Aug 27, 2009 · In this study, we provide evidence that the gene ABCC11 (MRP8), which encodes an apical efflux pump, is crucial for the formation of the characteristic ...
[98]
Unraveling the universality of chemical fear communication
Abstract. Abundant evidence indicates that humans can communicate threat-related information to conspecifics through their body odors.
[99]
Mechanism of multidrug resistance to chemotherapy mediated by P ...
In general, ABC transporters, including P-gp, are expressed more highly in resistant tumors, which increases the chance of drug efflux. The high expression of P ...
[100]
Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance
P-gp can efflux chemotherapy agents and reduce intracellular drug levels (Ahmed et al., 2020), which is one of the major causes of chemo-resistance. The ...
[101]
ABC transporters affects tumor immune microenvironment to ...
This review provides an update about the pivotal roles of ABC transporters in regulating TIME and subsequently leading to drug resistance to cancer chemotherapy ...Abc Transporters Affects... · 4. Cytokines In Time... · 6. Abc Transporter Proteins...
[102]
ATP Binding Cassette transporters associated with chemoresistance
Sep 1, 2011 · The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia.
[103]
Colistin kills bacteria by targeting lipopolysaccharide in the ... - eLife
Apr 6, 2021 · Modulation of cytoplasmic lipopolysaccharide levels sensitises bacteria to polymyxin antibiotics, revealing a novel combination therapeutic ...
[104]
MsbA-dependent Translocation of Lipids across the Inner ...
MsbA is an essential ABC transporter in Escherichia coli required for exporting newly synthesized lipids from the inner to the outer membrane.
[105]
A Pan-Cancer Landscape of ABCG2 across Human Cancers - MDPI
Dec 15, 2022 · This pan-cancer study provides, for the first time, a comprehensive understanding of the multifunctionality of ABCG2 and unveils further details of the ...Missing: 2020s | Show results with:2020s<|control11|><|separator|>
[106]
ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives - MDPI
ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML ...
[107]
Molecular mechanisms of cystic fibrosis – how mutations lead to ...
Cystic fibrosis (CF) is the most common autosomal recessive disorder among Caucasians, affecting about 80,000 individuals worldwide. The frequency of this ...Missing: ΔF508 prevalence
[108]
Worldwide Genetic Analysis of the CFTR Region - Cell Press
Mutations at the cystic fibrosis transmembrane conductance regulator gene (CFTR) cause cystic fibrosis, the most prevalent severe genetic disorder in ...
[109]
Consensus on the use and interpretation of cystic fibrosis mutation ...
The most common mutation is F508del, previously termed ΔF508, which accounts for approximately two thirds of all CFTR alleles in patients with CF, with a ...
[110]
Three novel pathogenic ABCC2 mutations identified in two patients ...
Aug 24, 2022 · Dubin–Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the ABCC2 gene; it is characterized by chronic ...
[111]
Clinical characteristics and follow-up of a newborn with Dubin ...
Jan 26, 2024 · The syndrome is attributed to mutations in the ABCC2 gene, which impairs the hepatic secretion of conjugated bilirubin into bile. 12 , 13.
[112]
Clinical characteristics and ABCC2 genotype in Dubin-Johnson ...
Dubin-Johnson syndrome (DJS) is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene. It is characterized by chronic or intermittent ...Missing: export | Show results with:export<|separator|>
[113]
ABCD1 mutations and the X-linked adrenoleukodystrophy ... - PubMed
X-linked adrenoleukodystrophy (X-ALD) ... peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome
[114]
From gene to therapy: a review of deciphering the role of ABCD1 in ...
Nov 11, 2024 · X-ALD is a severe genetic disorder caused by ABCD1 mutations, resulting in the buildup of very-long-chain fatty acids, leading to significant neurological ...
[115]
An Overview of the Genetics of ABCA4 Retinopathies, an Evolving ...
Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner.Missing: export | Show results with:export
[116]
Stargardt disease - Orphanet
The prevalence is estimated at 1/8,000 - 1/10,000. Both sexes are ... Mutations in ABCA4 have been linked to a spectrum of phenotypes ranging from ...
[117]
Clinical spectrum, genetic complexity and therapeutic approaches ...
The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two ...
[118]
FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat ...
Jan 31, 2012 · KALYDECO (kuh-LYE-deh-koh) is approved for people with CF ages 6 and older who have at least one copy of the G551D mutation in the cystic ...
[119]
Cystic fibrosis transmembrane conductance regulator modulators
In January 2012, ivacaftor (Kalydeco, Vertex Pharmaceuticals, Boston, Massachusetts, USA) was the first CFTR modulator approved by the FDA. It is a potentiator ...
[120]
Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a ...
The first inhibitor (or more correctly referred to as a P-gp modulator) identified was the L-type calcium channel blocker verapamil (Tsuruo et al., 1982, 1983).Missing: Ca2+ blockade
[121]
ATP-binding cassette transporters in progression and clinical ...
Aug 7, 2018 · There are several reasons for the lack of success of the ABC transporters inhibition. Increased toxicity caused by off-target action in ...Missing: Ca2+ | Show results with:Ca2+
[122]
ABC Transporters in Multidrug Resistance and Pharmacokinetics ...
In this review, we focus on the role of ATP-binding cassette (ABC) transporters in MDR of cancer cells and the development of ABC efflux transporter inhibitors ...Missing: off- Ca2+ blockade
[123]
Factors Governing P-Glycoprotein-Mediated Drug–Drug Interactions ...
Moreover, IC50 values of tariquidar for transport inhibition were for each substrate similar in ABCB1- and Abcb1a-transfected cells (Figures 1C and 1D), which ...
[124]
The “Specific” P-Glycoprotein Inhibitor Tariquidar Is Also a Substrate ...
Oct 21, 2010 · Our results show that at low concentrations, tariquidar acts selectively as an inhibitor of P-gp and also as a substrate of BCRP.Missing: seminal | Show results with:seminal
[125]
Knockout of ABC transporters by CRISPR/Cas9 contributes to ... - NIH
CRISPR/Cas9, a low cost but more efficient and precise gene editing technology, was utilized to singly or doubly knockout the P-gp, BCRP, and MRP2 genes in ...
[126]
Multidrug resistance transporters P-gp and BCRP limit the efficacy of ...
May 1, 2024 · The ABCG2 gene knockout NCI-H460-ABCG2ko and NCI-H460/TPT10-ABCG2ko cells were previously generated by CRISPR-Cas9 system (Lei et al., 2020).
[127]
CRISPR technology: A versatile tool to model, screen, and reverse ...
CRISPR gene-editing technology has proven to be a useful tool to study cancer drug resistance mechanisms and target the responsible genes.
[128]
Improving cancer chemotherapy with modulators of ABC drug ... - NIH
ABC transporter modulators can be used in combination with chemotherapeutics to increase the effective intracellular concentration of anticancer drugs.
[129]
ATP-binding cassette transporter inhibitor potency and substrate ...
Aug 5, 2024 · Both elacridar and tariquidar inhibit ABCB1 better than ABCG2, as the IC50 values of both inhibitors are about 10-fold higher for ABCG2 than for ...Missing: seminal | Show results with:seminal
[130]
Tracing the structural evolution of eukaryotic ATP binding cassette ...
Nov 18, 2015 · We present a putative structural evolutionary path of eukaryote ABC transporters that will increase our understanding on their origin, divergence and function.Missing: AB | Show results with:AB
[131]
Evolutionary history of ATP‐binding cassette proteins - FEBS Press
Nov 3, 2020 · The P-loop NTPases have a conserved motif called the Phosphate-binding loop or Walker A motif (GxxGxGKST) that plays a critical role in binding ...Missing: AB | Show results with:AB
[132]
ABC transporters are billion-year-old Maxwell Demons - Nature
Aug 8, 2023 · They are transmembrane proteins whose main function is the active, i.e., driven by ATP (adenosine triphosphate) hydrolysis, import or export of ...
[133]
New Insights into Evolution of the ABC Transporter Family in ... - NIH
Apr 11, 2022 · In plants, ABC transporters are one of the largest protein families and include eight subfamilies (ABCA-G and ABCI) [11,13]. During evolution, ...
[134]
Transporter Classification Database | Nucleic Acids Research
Nov 12, 2013 · The database contains more than 10 000 non-redundant proteins that represent all currently recognized families of transmembrane molecular transport systems.
[135]
Human ATP-binding cassette (ABC) transporter family
Apr 1, 2009 · The human genome carries 49 ABC genes, arranged in seven subfamilies, designated A to G (Figure 1 and Table 1). This diverse transporter family ...
[136]
https://www.annualreviews.org/doi/full/10.1146/annurev-biophys-111622-091232
[137]
ATP-dependent transporters: emerging players at the crossroads of ...
Oct 30, 2023 · Members of the ABCE and ABCF sub-families are notable in that they do not appear to function as transporters per se, but rather participate in ...<|control11|><|separator|>
[138]
ABC A-subfamily transporters: Structure, function and disease
ABC transporters constitute a family of evolutionarily highly conserved multispan proteins that mediate the translocation of defined substrates across membrane ...
[139]
ABC transporters: bacterial exporters-revisited five years on
This article will review the latest aspects of ABC proteins in Bacteria with an emphasis on procaryotic ABC export systems.
[140]
2021 update on ATP-binding cassette (ABC) transporters
New research reveals plant ABC proteins have critical functions throughout the plant life cycle. Some members of the ABCF and ABCI subfamilies play roles ...
[141]
ATP‐binding cassette transporters in nonmodel plants - Banasiak
Oct 6, 2021 · Initial work on plant ABC transporters concentrated on their roles in detoxification and pathogen defense via the transport of xenobiotics and ...Missing: AtABCI19 | Show results with:AtABCI19
[142]
The ABCs of Candida albicans Multidrug Transporter Cdr1 - PMC
Nov 30, 2015 · Of the six subfamilies of ABC transporters, ABCG/PDR is the largest, with nine members. Four members of the PDR subfamily have been ...
[143]
An update on ABC transporters of filamentous fungi
In this work, we review the individual subfamilies of ABC transporters in filamentous fungi regarding physiological substrates, clinical and agricultural ...
[144]
ABC proteins in yeast and fungal pathogens - Portland Press
Sep 7, 2011 · The PDR subfamily. The PDR subfamily is the largest ABC subfamily and contains two of the most extensively studied ABC proteins in yeast ...<|separator|>
[145]
The ABC transporter genes of Plasmodium falciparum and drug ...
To date, three full-length ABC transporter genes have been isolated from P. falciparum: two P-glycoprotein-like homologues, pfmdr1 and pfmdr2, and a homologue ...
[146]
The ABCs of multidrug resistance in malaria - ScienceDirect.com
Other Plasmodium ABC transporters in multidrug resistance. The location of the Plasmodium ABC transport proteins within the parasite are depicted in Figure 3.
[147]
ABC transporters involved in drug resistance in human parasites
Sep 7, 2011 · ABC proteins have been involved in clinical drug resistance in parasitic protozoa, including CQ resistance in Plasmodium falciparum and antimony ...
[148]
Learning the ABCs one at a time: structure and mechanism of ABC ...
ABC transporters harness the energy of ATP hydrolysis to drive the import of nutrients inside bacterial cells or the export of toxic compounds or essential ...
[149]
Molecular structure of human P-glycoprotein in the ATP-bound ...
Jan 25, 2018 · Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo–electron microscopy at 3.4-angstrom resolution.
[150]
Cryo-EM structure of P-glycoprotein bound to triple elacridar ...
In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules.
[151]
Effects of nucleotide binding to LmrA: A combined MAS-NMR and ...
Solution NMR on isolated LmrA-NBD shows residue specific effects of nucleotide binding. Carrying out NMR assignments (the correlation of a peak observed in an ...
[152]
Attempts to characterize the NBD heterodimer of MRP1: transient ...
Dimer formation between NBDs of ABC transporters, either as homo- or hetero-dimers, appears as a general rule of their structural organization and is required ...Missing: seminal | Show results with:seminal
[153]
Solid-State NMR Reveals Asymmetric ATP Hydrolysis in the ...
Jul 1, 2022 · disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. ... ATP hydrolysis on the ABC transporter NBD ...Introduction · Results · Discussion · Conclusions
[154]
Highly accurate protein structure prediction with AlphaFold - Nature
Jul 15, 2021 · Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure ...
[155]
Detergent-free systems for structural studies of membrane proteins
However, detergent-based approaches have significant drawbacks because they often lead to over-delipidation of membrane proteins, subsequent destabilization, ...
[156]
From in vitro towards in situ: structure‐based investigation of ABC ...
Nov 20, 2020 · This conundrum mainly arises from technical limitations confining all research to in vitro analysis of ABC transporters in detergent solutions ...
[157]
Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking ...
Oct 11, 2011 · LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1 ... Increased Atherosclerosis in ABCA1/apoE dKO Transplanted LDLr KO ...
[158]
Combined deficiency of ABCA1 and ABCG1 promotes foam cell ...
We bred mice with single or combined KO of Abca1 and Abcg1, transplanted ... atherosclerosis in C57BL/6 and apoE-knockout mice. Proc. Natl. Acad. Sci ...Abstract · Results · Discussion · Methods
[159]
Single amino acid substitutions in either YhjD or MsbA confer ...
Dec 18, 2007 · It was shown that increased levels of MsbA on a multicopy plasmid can directly rescue the auxotrophic parent strain from the otherwise lethal ...
[160]
CRISPR screens reveal convergent targeting strategies against ...
Jun 29, 2024 · Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic ...
[161]
Knockout of ABC transporters by CRISPR/Cas9 contributes to ...
Oct 27, 2022 · Knockout of ABC transporters by CRISPR/Cas9 contributes to reliable and accurate transporter substrate identification for drug discovery.
[162]
N-Terminal Extension and C-Terminal Domains Are Required for ...
We show that C. elegans ABCB6/HMT-1 localizes to the endosomal recycling system in intestinal cells, while the ABCB6/HMT-1 lacking the NTE domain tends to ...
[163]
Normal Formation of a Subset of Intestinal Granules in ...
Apr 29, 2009 · TAP-like (TAPL; ABCB9) is a half-type ATP-binding cassette (ABC) transporter that localizes in lysosome and putatively conveys peptides from ...
[164]
Association of Multidrug Resistance in Epilepsy with a ...
We have demonstrated that the C3435T polymorphism in ABCB1 is associated with drug resistance in epilepsy, irrespective of the type of epilepsy or antiepileptic ...
[165]
Genome-wide Association Study of Virologic Response with Efavirenz
An initial report identified an association between an ABCB1 polymorphism (which encodes P-glycoprotein) and virologic response to efavirenz-containing regimens ...