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ATP Binding Cassette Systems: Structures, Mechanisms, and Functions Cent. Eur. J. Biol.• 6(5) • 2011 • 785-801 DOI: 10.2478/s11535-011-0054-4 Central European Journal of Biology ATP binding cassette systems: structures, mechanisms, and functions Review Anke Licht*, Erwin Schneider* Department of Biology, Division of Microbial Physiology, Humboldt University of Berlin, D-10115 Berlin, Germany Received 31 March 2011; Accepted 02 June 2011 Abstract: ATP-binding cassette (ABC) systems are found in all three domains of life and in some giant viruses and form one of the largest protein superfamilies. Most family members are transport proteins that couple the free energy of ATP hydrolysis to the translocation of solutes across a biological membrane. The energizing module is also used to drive non-transport processes associated, e.g., with DNA repair and protein translation. Many ABC proteins are of considerable medical importance. In humans, dysfunction of at least eighteen out of 49 ABC transporters is associated with disease, such as cystic fibrosis, Tangier disease, adrenoleukodystrophy or Stargardt’s macular degeneration. In prokaryotes, ABC proteins confer resistance to antibiotics, secrete virulence factors and envelope components, or mediate the uptake of a large variety of nutrients. Canonical ABC transporters share a common structural organization comprising two transmembrane domains (TMDs) that form the translocation pore and two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP. In this Mini-Review, we summarize recent structural and biochemical data obtained from both prokaryotic and eukaryotic model systems. Keywords: ATP-binding cassette • Protein superfamily • Transport proteins • P-glycoprotein • Maltose transporter • ECF transporter • Prokaryotes • Eukaryotes • Disease © Versita Sp. z o.o. 1. Introduction size, the highest number of ABC systems is found in bacteria [1]. ATP-binding cassette (ABC) systems are found in all Canonical ABC transporters share a common three domains of life (bacteria, archaea and eukarya) structural organization comprising two transmembrane and some giant viruses and form one of the largest domains (TMDs) that form the translocation pathway protein superfamilies [1]. Most family members are and two nucleotide-binding domains (NBDs) that bind transport proteins that couple the free energy of ATP and hydrolyze ATP. Based on sequence comparison, hydrolysis to the translocation of solutes across a three classes of ABC systems that were probably biological membrane. However, the energizing module present in the last common ancestor of archaea, bacteria is also used to drive non-transport processes. The and eukarya have been proposed: class 1 comprises human genome includes 49 genes for ABC transporters transporters with fused TMDs and NBDs (exporters), in seven subfamilies (designated A-G), at least eighteen class 2 includes non-transport ABCs lacking TMDs and of which, when mutated, cause disease [2], while the class 3, (which is absent in eukaryotes) includes mainly genome of the gut bacterium Escherichia coli strain K-12 transporters with NBDs and TMDs formed by separate was predicted to encode 71 discrete ABC (transport) polypeptide chains (canonical importers) and some systems [3] (http://www1.pasteur.fr/recherche/unites/ bacterial exporters (Figure 1) (reviewed in [1]). pmtg/abc/database.iphtml). Substrates transported by ABC transporters are Plant genomes code for a high number of ABC diverse, such as sugars, amino acids, peptides, vitamins, systems with more than 120 in both Arabidopsis thaliana ions, hormones, xenobiotics, antimicrobial drugs, and Oryza sativa (rice) [4]. Yet, in relation to genome chemotherapeutic agents, and even large polypeptides, * E-mail: [email protected] ; [email protected] 785 ATP binding cassette systems: structures, mechanisms, and functions Figure 1. Modular organization of ATP-binding cassette systems. Members of the ABC superfamily are classified into exporters, importers and non-transporting proteins. Exporters and canonical importers consist of two transmembrane domains (TMD, in green) and two nucleotide-binding domains (NBD, in purple). In exporters, the substrate (filled black circles) might enter the translocation pore from the cytoplasmic side or from within the membrane, depending on its chemical nature. As a representative, the crystal structure of mouse P-glycoprotein (MDR1) (PDB code 3G5U) is shown. MDR1 is a full transporter with all four domains fused in a single polypeptide chain (see also Figure 3A). Canonical ABC importers require an extracytoplasmic solute receptor (in orange). As a representative, the structure of the molybdate/tungstate transporter of Archaeoglobus fulgidus is shown, consisting of a homodimer each of the TMD, ModB (green), the NBD, ModC (violet), and the receptor, ModA (orange) (PDB code 2ONK). ECF (energy coupling factor) type ABC importers consist of a substrate-specific transmembrane domain (S component), a small transmembrane domain (T component), and two copies of a nucleotide binding domain (NBD, also termed A and A’ components). The structure of the S-component RibU of the riboflavin transporter of Staphylococcus aureus with bound substrate (yellow, space-fill representation) is shown (PDB code 3P5N). Non-transporting ABC proteins consist of two fused NBD dimers and additional domains (in light yellow) but lack TMDs. As a representative, the structure of the catalytic domain of the DNA repair protein Rad50 of Pyrococcus furiosus is depicted in complex with two ATP molecules (red) (PDB code 1F2U). N-and C-terminal domains are coloured purple and cyan, respectively. Structures are not necessarily drawn to scale. linking these proteins to various cellular functions to sense the γ–phosphate, bind the necessary divalent that range from energy supply to osmoregulation, cation (usually Mg2+) and attack water [6]. The LSGGQ detoxification and virulence. motif interacts with the γ–phosphate and is involved in ATP In ABC transporters, substrate specificity is hydrolysis as known from the arginine finger observed in accomplished by the TMDs, which display basically no other P-loop ATPases [7]. In the active NBD dimer, ATP is sequence homologies and feature varying numbers of sandwiched between the Walker A motif of one monomer transmembrane helices (5-10) among different systems. and the LSGGQ motif of the opposing monomer [6] On the contrary, the ability to bind and hydrolyze ATP, thus (Figure 2C). providing the energy stroke for substrate translocation or As a unique feature of ABC transporters, the so- non-transport processes, is a common feature of the NBDs, called ‘coupling helices’ or ‘EAA’ motifs in canonical which share several conserved motifs in all ABC systems importers, localized to the last cytoplasmic loop of the (Figure 2A). With regard to three-dimensional structures, importer TMDs, and the first and last cytoplasmic loops NBDs can be subdivided in a RecA-like subdomain, of exporter TMDs, are part of the NBD–TMD interface. containing the conserved Walker A (also known as ‘P-loop’) The ‘coupling helices’ are architecturally conserved and B motifs which contribute substantially to nucleotide elements, which interact with the Q-loops to couple binding, and an α-helical subdomain encompassing the binding and hydrolysis of ATP at the NBDs to additional conserved motifs. Among these motifs are the conformational changes in the TMDs. Q-loop (containing a conserved glutamine residue) and ABC exporters are mostly NBD-TMD fusion proteins the signature sequence (‘LSGGQ’) by which members that form either homo- or heterodimers (‘half transporter’) of the family can be identified [5] (Figure 2B). The or all four domains are located on one polypeptide chain Q-loop, located at the interface to the TMDs, is known (Figure 3A). 786 A. Licht, E. Schneider Figure 2. Conserved motifs of NBDs. A. Linear representation of an NBD, with assignment of the main functional sites. Conserved sequences are in parentheses, using the one letter code for amino acids (x, any residue; h, hydrophobic residues). Motifs involved in nucleotide binding are given in red. B. Structure of an NBD monomer (ArtP of Geobacillus stearothermophilus, PDB code 2OUK) indicating the localization of conserved motifs as shown in (A). C. Structure of an NBD dimer (MalK2 of E. coli, PDB code 1Q12; regulatory C-terminal domains are omitted) with two ATP molecules (blue, space fill representation) sandwiched between the Walker A motif of one monomer (A chain, in yellow) and the ABC signature of the opposing monomer (B chain, in light blue). Figure 3. Diversity in molecular architecture of ABC transporters. A. ABC exporters might be homo- (Sav1866) or heterodimers (TAP1/TAP2) of a TMD-NBD fusion protein. Alternatively, all four domains can be fused into a single polypeptide chain (MDR1), e.g. in the order of TMD1-NBD1-TMD2-NBD2 or, as in case of CFTR, an additional regulatory domain (in yellow) is connecting NBD1 with TMD2. B. Canonical ABC importers can exist in all possible combinations of separately expressed or fused TMDs and NBDs. The extracellular solute receptors are either soluble proteins, lipid-anchored, membrane-associated via an N-terminal transmembrane α-helix or fused to a TMD (not depicted) [8]. Substrates transported by the indicated systems are given in parentheses. Colour code as in Figure 1. Canonical (class 3) ABC import systems, hitherto architecture is diverse, i.e. all possible combinations exist confined to prokaryotes, are dependent on high-affinity, (Figure 3B). Canonical importers
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