The bacterial ABC (ATP-binding cassette) importers mediate nutrient uptake and some are essential for survival in environments where nutrients are limited, such as in the human body. Although ABC importers exhibit remarkable versatility in the substrates that they can transport, they appear to share a similar multisubunit architecture and mechanism of energization by ATP hydrolysis. This chapter will provide both basic understanding and up-to-date information on the structure, mechanism and regulation of this important family of proteins.

Introduction

One of the most basic features of a living cell is the selective permeability of solutes across the membrane, mediated by transport proteins (also called permeases). There are four major types of transport proteins: (i) passive channels that facilitate transport down a concentration gradient (more common in eukaryotes), (ii) primary active transporters that use a primary energy source such as ATP, (iii) secondary active transporters that use a secondary energy source such as an ion gradient across the membrane (a sodium- or proton-motive force), and (iv) group translocators that modify their substrates during transport (such as glucose uptake in bacteria) [1]. Between 3 and 16% of open reading frames in bacterial genomes are predicted to encode transport proteins, the average percentage (9%) is higher than that in archaeal (7%) or eukaryotic genomes (4%) [2]. The number of transport proteins correlates with the lifestyle of the micro-organism, with the plant/soil-associated species having the largest number and the obligate intracellular species having the smallest number [3].

The ABC (ATP-binding cassette) transporter superfamily is one of the largest families among transport proteins, widely distributed in all the three domains of life, i.e. Archaea, Bacteria and Eukarya. ABC transporters can recognize almost any solute of biological interest, regardless of whether it is organic or inorganic, large or small [1]. In Escherichia coli, 536 genes encode transport proteins (13% of the genome), 210 of which encode ABC transporters (5% of the genome) [4,5]. The percentage of ABC transporters is even higher in some plant/soil-associated species [4]. The ABC, also referred to as an NBD (nucleotide-binding domain), is a highly conserved protein domain of approximately 215 amino acids, serving as an ancient and ubiquitous energizing module. Using ATP as fuel, ABC superfamily members couple this module to a variety of biological functions, including solute transport [6].

ABC transporters can be divided into importers and exporters on the basis of the polarity of solute movement. Unlike ABC exporters, which are ubiquitous, ABC importers are found mostly in bacteria and are crucial in mediating uptake of solutes including monosaccharides, disaccharides, polysaccharides, amino acids, oligopeptides, phospholipids, cholesterol, nucleosides, metal ions, oxyanions and vitamins. Although autotrophic bacteria generally lack transporters for carbohydrates, amino acids and nucleosides, they encode a full spectrum of transporters for ions, ammonium, phosphate and sulfate [3].

The pathogenesis of bacterial diseases has been likened to a molecular arms race between bacteria and host in which bacterial ABC importers play a critical role in nutrient acquisition, providing energy for growth. A number of ABC importers have been identified as virulence factors in pathogenic species, implying that these micro-organisms cannot grow in the host environment without specific nutrients. These importers include the haem transporter of Staphylococcus aureus [7], the glutamine transporter of Salmonella enterica serotype Typhimurium and Streptococcus agalactiae [8,9], and the maltodextrin transporter of Streptococcus pyogenes and Vibrio cholerae [10,11]. ABC importers can be good targets for drug development since they are essentially unique to bacteria and are accessible without penetrating the cytoplasmic membrane.

Architecture

ABC importers comprise two TMDs (transmembrane domains) that form the solute-translocation pathway and two NBDs that hydrolyse ATP in the cytoplasm. TMDs and NBDs can form homodimeric or heterodimeric complexes and can exist as separate subunits or be fused together in different ways [12]. Most ABC importers rely on an extracytoplasmic SBP (solute-binding protein) to function, and are known as SBP-dependent transport systems. Usually each protein in the system is named with the solute followed by a designated capital letter. For example, in the maltose/maltodextrin-import system MalEFGK2, MalE is the SBP, MalF and MalG are the TMDs, and two MalKs form a dimer of NBDs; in the molybdate-import system ModAB2C2, ModA is the SBP, a ModB dimer forms the TMDs, and a ModC dimer forms the NBDs.

The genes encoding the TMD, NBD and SBP for a specific transporter are often organized in one locus. However, there are exceptions. For example, the maltose and cellobiose importers of Streptomyces lividans and Streptomyces reticuli share the same NBD, MsiK (multiple sugar import), and the msiK gene is separated from the binding protein gene cpbE [13]. Similarly, choline/betaine/carnitine (cbc) importers of Pseudomonas syringae and Pseudomonas aeruginosa share both NBDs and TMDs, and the genes encoding betaine-binding protein BetX and carnitine-binding protein CaiX are separated from the cbc locus in the genome [14].

Three independent phylogenetic studies using SBPs, TMDs or NBDs defined eight clusters of bacterial ABC importer systems according to their sequence similarities, with each cluster showing distinct solute specificity [1517]. Later, in the TC (transporter classification) system, the ABC importers were classified into 20 families on the basis of both function and phylogeny [1]. The SBP-dependent importers appear to originate from a common ancestor more than 3 billion years ago. Different importer systems appear to have evolved through duplication events, whereas domain insertion and deletion events are exceptionally rare. The SBP, TMD and NBD components of the same system often co-evolve in the same operon, with little or no shuffling between different systems. Occasionally, local duplication events gave rise to heterodimers of TMDs and NBDs. Many of these events happened before the divergence of Gram-positive from Gram-negative bacteria [17].

Although most of the bacterial importers require an SBP, there are exceptions, most notably a novel class of ABC transporters termed ECF (energy-coupling factor) transporters. Whereas these transporters contain a canonical NBD dimer, the TMDs are thought to differentiate into a substrate-specific subunit (S) that binds substrate with high affinity and an energy-coupling subunit (T) that is sometimes shared between transporters [18]. ECF ABC transporters are relatively abundant in Gram-positive bacteria, but are rare in Gram-negative bacteria, transporting solutes including nickel (NikMNOQ from Rhodobacter capsulatus), cobalt (CbiMNOQ from Salmonella), vitamins (BioMNY from Sinorhizobium meliloti and Rhizobium etli) and tryptophan [1921]. Interestingly, in the SBP-dependent maltose- and histidine-transport systems, mutants have been isolated that have gained the ability to transport in the absence of their binding proteins. These mutants retain substrate specificity, but with greatly decreased affinity, suggesting that, whereas the SBPs contain a high-affinity substrate-binding site, the membrane transporters also contain a separate lower-affinity site [2224].

High-resolution structures

Several ABC importers have been successfully crystallized, yielding high-resolution structures by X-ray crystallography, including the vitamin B12 importer BtuCDF from E. coli [25,26], the metal-chelate importer HI1470/1 from Haemophilus influenzae [27], the molybdate/tungstate importer ModAB2C2 from both Archaeoglobus fulgidus and Methanosarcina acetivorans [28,29], the maltose/maltodextrin importer MalEFGK2 from E. coli [30,31] and the methionine importer MetNI from E. coli [32] (Figure 1). Because of the dimeric architecture in NBDs and TMDs, it is not surprising that an overall two-fold symmetry was observed in all of these crystals.

Gallery of ABC importer crystals

Figure 1
Gallery of ABC importer crystals

Protein backbones are shown as ribbons: blue and yellow, TMDs; red and green, NBDs; pink and cyan, C-terminal regulatory domains of NBDs; magenta, SBPs. Note the conserved EAA motif (short horizontal blue and yellow helices at the TMD–NBD interface). (A) The metal-chelate importer HI1470/1 from H. influenzae (PDB code 2NQ2) [27]. (B) The vitamin B12 importer BtuCD from E. coli (PDB code 1L7V) [25]. (C) BtuCD with its SBP BtuF (PDB code 2QI9) [26]. (D) The methionine importer MetNI from E. coli (PDB code 3DHW) [32]. (E) The molybdate/tungstate importer ModB2C2 from M. acetivorans, with its substrate tungstate (orange spheres) bound to the regulatory domain (PDB code 3D31) [29]. (F) The molybdate/tungstate importer ModB2C2 and the substrate-loaded SBP ModA from A. fulgidus (PDB code 2ONK) [28]. (G) The maltose/maltodextrin importer MalFGK2 from E. coli (PDB code 3FH6) [31]. (H) MalFGK2 and MalE complex, with maltose (orange spheres) bound to MalF and ATP (purple spheres) sandwiched by NBDs (PDB code 2R6G) [30]. Figures prepared using PyMOL (http://www.pymol.org).

Figure 1
Gallery of ABC importer crystals

Protein backbones are shown as ribbons: blue and yellow, TMDs; red and green, NBDs; pink and cyan, C-terminal regulatory domains of NBDs; magenta, SBPs. Note the conserved EAA motif (short horizontal blue and yellow helices at the TMD–NBD interface). (A) The metal-chelate importer HI1470/1 from H. influenzae (PDB code 2NQ2) [27]. (B) The vitamin B12 importer BtuCD from E. coli (PDB code 1L7V) [25]. (C) BtuCD with its SBP BtuF (PDB code 2QI9) [26]. (D) The methionine importer MetNI from E. coli (PDB code 3DHW) [32]. (E) The molybdate/tungstate importer ModB2C2 from M. acetivorans, with its substrate tungstate (orange spheres) bound to the regulatory domain (PDB code 3D31) [29]. (F) The molybdate/tungstate importer ModB2C2 and the substrate-loaded SBP ModA from A. fulgidus (PDB code 2ONK) [28]. (G) The maltose/maltodextrin importer MalFGK2 from E. coli (PDB code 3FH6) [31]. (H) MalFGK2 and MalE complex, with maltose (orange spheres) bound to MalF and ATP (purple spheres) sandwiched by NBDs (PDB code 2R6G) [30]. Figures prepared using PyMOL (http://www.pymol.org).

As the ATP-binding cassette, NBDs are the most conserved domains of ABC importers. NBDs can be divided into two subdomains: a RecA-like subdomain common in many ATPases, which contains the nucleotide-binding Walker A and Walker B motifs [33,34], and a helical subdomain specific to ABC proteins, which contains the ABC family signature motif LSGGQ. Because the NBDs are dimeric, there are two ATP-binding sites in the NBDs, both are located between the Walker A motif of one subunit and the LSGGQ motif of the opposite subunit [35,36]. In the one structure with ATP bound (Figure 1H), the NBD dimer is closed with two ATPs bound along the dimer interface [30]. In structures lacking nucleotide, the NBD dimer is open (Figure 1). Many bacterial NBDs have an extra C-terminal domain involved in regulation, including the E. coli MetNI, M. acetivorans ModBC and E. coli MalEFGK2 (Figures 1D, 1E, 1G and 1H).

TMDs are the least conserved domains of ABC importers, although only two unique folds have been discovered to date. HI1470/1 and BtuCD have 20 transmembrane helices and share the same fold (Figures 1A1C), although the helices are splayed outwards in the structure of BtuCD and inwards in HI1470/1. This difference is suggestive of an alternating-access mechanism for substrate translocation in which the outward-facing conformation would receive substrate from the binding protein into a permeation pathway and the inward-facing conformation would release substrate inside the cell [25,27]. MetNI, ModB2C2 and MalFGK2, with ten, twelve and fourteen transmembrane helices respectively, all contain a core of helices with the same fold, although both inward-facing and outward-facing conformations are seen (Figures 1D1H). The final cytoplasmic loop contains an EAA motif that is highly conserved among these TMDs, making contact with the Q-loop of the NBD at the NBD–TMD interface. The Q-loop lies between the RecA-like subdomain and the helical subdomain and may play a role in subdomain rotation in response to ATP binding [36]. The EAA motif plays an important role in coupling the NBDs to the TMDs [37,38]. The E. coli MalF protein has a periplasmic loop folding into a domain that forms extensive contacts with the periplasmic SBP and may be important for docking of the SBP to the transporter. Interestingly, in sequence alignments of maltose transporters, this loop is lacking in Gram-positive bacteria where SBPs are often tethered to the membrane.

All SBPs characterized to date have two domains or lobes (N- and C-terminal lobes), with one or more polypeptide chains connecting the two lobes. Structurally, SBPs can be divided into three types on the basis of the linkage between the two lobes [39]. In type I and type II SBPs, the lobes are separated in the ligand-free conformation, with an open cleft between them. Ligand binding in the cleft induces closure of the two lobes. For type III SBPs, ligand binding still occurs in the cleft, but the domain movement is small [40]. In the three SBP-docked structures (Figures 1C, 1F and 1H), both lobes of the SBPs bind to the transporters, and the clefts of the SBPs align with the permeation pathway through the centre of the TMDs.

Model of transport cycle

A cartoon describing the transport cycle is shown in Figure 2, based primarily on the well-characterized E. coli MalEFGK2 system. The details of three major steps are described below.

Model for maltose transport by E. coli MalFGK2 and its SBP (MalE)

Figure 2
Model for maltose transport by E. coli MalFGK2 and its SBP (MalE)

(A) In the resting state, the MalK dimer is open and MalFG opens inward; SBP, in a closed conformation with maltose (black circle) bound, initiates transport and hydrolysis. (B) SBP stimulates the ATPase activity by stabilizing the catalytic transition state for ATP hydrolysis in which MalK dimer is closed, MalFG opens outwards, and SBP is tightly bound in an open conformation. (C) The transporter returns to resting state following ATP hydrolysis, maltose is transported, and SBP is released. Modified from [51] with permission.

Figure 2
Model for maltose transport by E. coli MalFGK2 and its SBP (MalE)

(A) In the resting state, the MalK dimer is open and MalFG opens inward; SBP, in a closed conformation with maltose (black circle) bound, initiates transport and hydrolysis. (B) SBP stimulates the ATPase activity by stabilizing the catalytic transition state for ATP hydrolysis in which MalK dimer is closed, MalFG opens outwards, and SBP is tightly bound in an open conformation. (C) The transporter returns to resting state following ATP hydrolysis, maltose is transported, and SBP is released. Modified from [51] with permission.

(i) Resting state and SBP docking

SBPs are essential components that confer solute specificity and high affinity on the importer systems. Some SBPs are highly specific for one ligand, e.g. oxyanions such as phosphate and sulfate [4143], whereas others can bind a range of similar ligands, e.g. maltodextrins, oligopeptides and branched-chain amino acids [4446]. In Gram-negative bacteria, SBPs are soluble proteins located in the periplasmic space between the inner and outer membranes. In Gram-positive bacteria, SBPs are either tethered to the cytoplasmic membrane as lipoproteins or fused to the TMDs [47]. Typically 2% or more of a Gram-positive bacterial genome encodes lipoproteins, with 40% of the putative lipoproteins being SBPs associated with ABC importers. Lipid modification is triggered by the presence of a lipobox motif (L−3-[A/S/T]−2-[G/A]−1-C+1) in the N-terminal signal sequence directing SBP secretion. A lipid group is covalently linked to the thiol group of the C+1 following secretion, and the rest of the signal peptide is cleaved [48].

In the resting state (Figure 1G), the TMDs (MalFG) are inward-facing, exposing a centrally located maltose-binding site in MalF to the cytoplasm, and the NBDs (MalK dimer) are open, even though ATP may be bound [31,49]. The docking of closed liganded SBP initiates the transport cycle by stimulating ATP hydrolysis [23,50]. Since the sequences of the SBPs' N-terminal lobes are much more conserved than those of the C-terminal lobes [15], it is tempting to propose that the N-terminal lobe plays an additional role, perhaps in initial recognition of the TMDs [51].

(ii) Transition state

SBP stimulates the ATPase activity by stabilizing the catalytic transition state in which the MalFG permeation pathway is outward-facing, the MalK dimer is closed, and SBP is tightly bound in an open conformation [30] (Figure 1H). Although ATP alone can induce the isolated MalK dimer to close [35], both ATP and SBP are needed to induce MalK closure and the concerted global conformational changes in intact transporters [49,51]. The transition state, seen in the crystal, can be stabilized by using ATP in the absence of Mg2+ or the non-hydrolysable Mg–AMP-PNP (adenosine 5′-[β,γ-imido]triphosphate) as an ATP analogue, and it can be stably trapped by adding vanadate as a transition-state analogue for the γ-phosphate of ATP, or by mutating an important catalytic residue (Glu159) in MalK. Vanadate-induced photocleavage of the protein backbone in both the Walker A and LSGGQ motif confirms that ATP hydrolysis occurs in this closed conformation [52]. In the outward-facing MalEFGK2 structure, an enclosed cavity is formed between the TMDs and SBP, which encompasses both the maltose-binding site in the SBP and the maltose-binding site in MalF. A periplasmic loop of MalG appears to reach into the binding site in the SBP, possibly preventing re-diffusion of the released substrate back into the SBP, and may be responsible for the transfer of substrate from the SBP to the transmembrane region, where it is seen bound to MalF [30]. The demonstration of a maltose-binding site in MalF confirms that the TMDs can play a role in solute recognition, as was suggested by the solute specificity of the SBP-independent mutants [22].

ATP-bound structures of isolated NBDs and intact transporters all show ATP bound at both sites [30,35,53,54], and the positive co-operativity seen in the maltose and histidine transporters also indicates that ATP occupies both sites before the NBDs hydrolyse ATP [55,56]. During ATP hydrolysis, however, it is debatable whether hydrolysis occurs to one ATP or both ATPs. The mechanism of ATP hydrolysis, whether it is general base catalysis mediated by a conserved glutamate residue (Glu159 in MalK) or substrate-assisted catalysis, is also an open question [6].

(iii) Post-hydrolysis state and resetting

Following ATP hydrolysis, maltose is transported, and SBP disengages as the transporter returns to the resting state. A post-hydrolysis state before ADP release has been proposed, with MalE still bound and the MalK dimer in a semi-open configuration [49,57]. Note that, in Gram-positive bacteria, the SBPs are often tethered to the membrane or fused to the transporter so that release of SBPs does not necessarily occur.

Since ATP hydrolysis occurs in the closed NBD dimer, it is tightly coupled to the SBP-induced conformational change from inward-facing to outward-facing and therefore to substrate transport, because a closed liganded binding protein would be expected to deliver substrate to the transporter in each catalytic cycle. Unliganded SBPs also can dock on to the importers, but ideally should not induce a change to the outward-facing conformation, or ATP would be consumed in a futile cycle. However, unliganded SBPs have been experimentally shown to stimulate ATP hydrolysis weakly; this is likely to be due to a very small population of transporters that progress far enough toward the transition-state conformation to engage directly in high-affinity binding with the open SBPs [58].

A distinct model for the BtuCDF system

In contrast with the type I and type II SBPs, which interact with their transporters in the resting state with low affinity (Kd≍10−4 M), the unliganded type III SBP BtuF forms a high-affinity complex with the 20-transmembrane-helix vitamin B12 importer BtuCD from E. coli (Kd≍10−13 M) even in the absence of ATP [59,60]. The structurally similar metal-chelate importer HI1470/1 from H. influenzae also binds its type III SBP with high affinity in the resting state (Kd≍10−9 M) [60], suggesting that high-affinity binding may be a general feature of these SBPs, which fail to undergo the well-characterized domain rotation of the type I and II SBPs. The presence of substrate and especially ATP greatly accelerates the dissociation of this high-affinity complex. These differences suggest that the translocation cycle for transporters using a type III SBP may be somewhat distinct from the model just proposed for maltose and related ABC transporters, even though the structure of the NBD dimer is highly conserved.

Involvement of ABC importer components in regulatory processes

Regulatory interactions between a transcription factor and an ABC importer

The E. coli MalEFGK2 system is one of the best-studied systems for ABC transporter regulation. In E. coli, the MalT protein activates all mal promoters and plays a central role in maltodextrin uptake and metabolism [61]. All genes regulated by MalT belong to the maltose regulon, many of which are organized in clusters. One of the clusters, the malB region, contains two oppositely oriented operons, with malE, malF and malG genes transcribed counterclockwise and malK, lamB and malM genes transcribed clockwise. Their transcription start sites are 271 bp apart. The malEFG and malK genes encode the ABC importer. The malM gene encodes an unknown periplasmic protein. The lamB gene encodes an outer membrane channel, allowing passage of long-chain maltodextrins across the outer membrane. Interestingly, the λ phage uses the LamB channel as its receptor to invade the cell.

MalT is a purely positive regulator, stimulating transcription by activating RNA polymerase. It recognizes the MalT box, 5′-GGA(G/T)GA-3′, 38 bp upstream of the transcriptional start point, and two further upstream repeats with the sequence 5′-GGGGA(T/G)GAGG-3′. These conserved sequences are found in the malEFG and malK operons, together with three essential cAMP–CAP (catabolite activator protein)-binding sites [62]. MalT is composed of four domains, and it equilibrates between an inactive monomeric form and an active maltotriose/ATP-bound form that will multimerize. Maltotriose, the inducer that binds MalT, can be synthesized endogenously to enable a basal level of mal expression in E. coli.

MalK serves not only as the energizing module of the transporter, but also as a repressor of MalT [61]. It has been proposed that MalK interacts with MalT through two distinct contacts: the NBD and C-terminal regulatory domain in MalK, and the DT1 and DT3 domains in MalT [63]. Hence, in the absence of maltose and therefore of transport activity, MalT is stabilized by MalK as an inactive monomer. When maltose is present and transported, MalK undergoes conformational changes, disengaging MalT which can become activated and multimerize, stimulating the transcription of the maltose regulon. In essence, the full induction of the regulon is connected to solute import itself. In the glycerol 3-phosphate importer system, UgpC may regulate the ugp operons similarly to MalK [61].

Examples of cross-talk between importers

Glucose is a preferred energy and carbon source as compared with maltodextrins in E. coli metabolism, therefore maltodextrin uptake and catabolism are repressed when glucose is available. Glucose is imported by the phosphoenolpyruvate-dependent glucose phosphotransferase system (a group translocator). Import of glucose leads to the dephosphorylation of the EIIAGlc protein via phosphotransfer, and the non-phosphorylated EIIAGlc can interact with the C-terminal regulatory domain of MalK, inactivating the maltodextrin importer [64]. In addition, EIIAGlc controls adenylate cyclase through phosphorylation (activation) and dephosphorylation (inactivation), which in turn regulates the intracellular cAMP levels. The cAMP–CAP complex is required for the expression of malT, which controls the expression of all mal operons, including malEFG and malK [61].

SBPs and chemotaxis

Several SBPs have an additional role in the regulation of bacterial chemotaxis, which is the mechanism by which motile bacteria, such as E. coli and Salmonella Typhimurium, can respond to environmental chemical gradients by moving towards attractants or away from repellents. Chemotaxis is mediated by chemoreceptor proteins (usually homodimers) on the cytoplasmic membrane. Ligand binding to the chemoreceptors, either directly or indirectly via SBPs of ABC importer systems, triggers conformational changes, which are transmitted to modulate the autophosphorylation rate of a bound histidine kinase in the cytoplasm, eventually leading to a change of the rotational state of the flagellar rotary motor. SBPs of the maltose, ribose, glucose/galactose and dipeptide importer systems are known to interact with chemoreceptors [65].

The Tar protein of E. coli provides a well-established model system for chemoreceptors. It generates responses to two distinct ligands: aspartate and maltose. Aspartate binds directly to helix 4 of Tar and pushes this transmembrane helix downward by approximately 1.6 Å (1 Å=0.1 nm) [66]. Maltose binds to MalE of the MalEFGK2 system, then MalE in its closed conformation docks on to the Tar receptor, pushing down on helix 4 similarly to aspartate [67].

Trans-inhibition

Certain ABC importers are inhibited by their solutes on the trans side (cytoplasmic side) of the membrane, a process termed trans-inhibition. This type of inhibition results in a decrease of the transport rate as the solute accumulates. Trans-inhibition has been reported for various ion and amino acid importers. The ATPase activity of the molybdate/tungstate importer ModB2C2 from M. acetivorans is decreased by 80% in the presence of 5 μM molybdate or tungstate, and the structure of this protein reveals the basis of trans-inhibition (Figure 1E) [29]. Similar to MalK, the NBD ModC also contains a C-terminal regulatory domain. The regulatory domains form two tungstate-binding pockets and binding of substrate can apparently lock the transporter in an inward-facing conformation, with the ATP-binding motifs of the NBDs separated further than in the resting state, thereby preventing ATP hydrolysis and tungstate transport. The methionine importer MetNI from E. coli has been crystallized with substrate similarly bound to its NBD regulatory domains, adding further support to this regulation model [32] (Figure 1D).

Conclusions

Bacteria can colonize almost every environmental niche, and the need for specific ABC importers can vary greatly, depending on nutrient availability. The combination of relatively recent high-resolution structures, paired with a long history of careful biochemical and genetic analyses, have provided great insight into their architecture and mechanism. Nucleotide-dependent closure of two highly conserved NBDs probably drives conformational changes in the transmembrane region of these importers that alternates access to a translocation pathway that can move solutes across the membrane. Two distinct classes of importers have been crystallized so far, and further biochemical, biophysical and bioinformatic approaches will lead to a better understanding of these and other novel classes of ABC importers. Better understanding of transport mechanisms will, in turn, ultimately reveal novel therapeutic strategies to treat bacterial diseases.

Summary

  • ABC importers are widespread in bacteria and display remarkable solute versatility.

  • ABC importers comprise two TMDs that form the solute-translocation pathway and two NBDs that hydrolyse ATP in the cytoplasm. Most ABC importers rely on an extracytoplasmic SBP for function.

  • ABCs are an ancient family and genes encoding different components of the same system often co-evolved.

  • ABC importers alternate between an inward-facing conformation and an outward-facing conformation in a catalytic cycle, coupling ATP hydrolysis to solute transport.

  • ABC importer components are involved in diverse regulatory processes that couple uptake to both the availability of and the need for a particular nutrient.

This work was supported by the National Institutes of Health [grant number GM070515 (to A.L.D.)], and J.C. was supported by a Purdue Research Grant.

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