Abc transportadores

Review

TRENDS in Microbiology

Vol.15 No.10

Molecular Machines of the Cell

ABC transporters: how small machines do a big job
Amy L. Davidson1 and Peter C. Maloney2
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Department of Chemistry and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA Department of Physiology, Johns Hopkins Medical School, 725 North Wolfe Street, Baltimore, MD 21205–2195, USATransporters from the ATP-binding cassette (ABC) superfamily operate in all organisms, from bacteria to humans, to pump substances across biological membranes. Recent high-resolution views of ABC transporters in different conformational states provide clues as to how ATP might be used to drive the structural reorganizations that accompany membrane transport. Importantly, it now appears that aputative translocation pathway running through the center of the transporter might be gated alternately, either at the inside or the outside of the cytoplasmic membrane, coupling substrate translocation to a cycle of ATP-dependent conformational changes. ATP binding and ATP hydrolysis have distinct roles in this cycle: binding favors the outwardfacing orientation, whereas hydrolysis returns thetransporter to an inward-facing conformation. A large family of transporters ATP-binding cassette (ABC) transporters are a class of small molecular machines that use energy from ATP hydrolysis to pump an unusually diverse set of compounds across biological membranes. The term ’ATP-binding cassette’ was not given to this large superfamily until 1990 [1], but the study of these transporters began decadesearlier, with the discovery of ATP-dependent nutrient uptake mediated by systems associated with high-affinity binding proteins in the periplasm of Gram-negative bacteria [2]. In bacteria, such importers can accumulate nutrients (sugars or amino acids typically) against gradients as large as 106:1 [3], consistent with the use of ATP rather than the protonmotive force as a source of energy (Box 1).Bacteria also use ABC transporters to remove various compounds from the cytoplasm. These export systems can be segregated into two general groups – those that secrete virulence proteins [4] and those that extrude small hydrophobic compounds, some of which have antimicrobial activity [5]. Because members of this second group display rather broad substrate specificity, they might also, by happenstance,contribute to multiple-drug resistance. ABC transporters are also found in eukaryotes,where they function in export from the cytoplasm. In humans, for example, ABC transporters are known to have a role in the excretion of xenobiotics (and therefore multiple-drug resistance), cholesterol transport and peptide movement
Corresponding author: Maloney, P.C. (pmaloney@jhmi.edu). Available online 24October 2007.
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into the endoplasmic reticulum. Furthermore, mutations in a growing number of ABC transporters have now been associated with human disease, including cystic fibrosis, hyperinsulinemia, macular degeneration and Tangier disease [6]. The core ABC transporter, which is associated with the membrane, is built up from two kinds of units – a pair of transmembrane (TM)modules that surround and define a permeation pathway and a pair of peripheral modules that bind and hydrolyze ATP. These modules can be individual subunits or can comprise separate domains within a larger polypeptide. For example, among the importers (prokaryotes), these four functional domains are most often encoded separately, although one might find variants that contain fusions of the TM domainsor fusions of the ATPase domains. By contrast, in exporters (prokaryotes and eukaryotes), a single gene usually encodes both a single TM domain with a partner ATPase domain. In these cases, the functional transporter might be a homodimer of a single polypeptide or a heterodimer of two distinct polypeptides [7]. Each TM domain typically contains six membranespanning a-helices, giving a total of...