تنوع انتقال دهنده های ABC: وارد کنندگان نوع I، II و III Diversity in ABC transporters: Type I, II and III importers

Introduction ABC transporters, present in all organisms, represent one of the largest transmembrane spanning super-families. ABC stands for ATP-binding cassette due to the family’s characteristic ability to bind and hydrolyze ATP in order to transport substrates across the lipid bilayer (Higgins, 1992). Found in both prokaryotes and eukaryotes, the well-studied ABC exporters, play a fundamental role in biological processes (Dean et al., 2001), are associated with multidrug resistance (Eckford & Sharom, 2009; Kerr et al., 2010; Seeger & van Veen, 2009), several human diseases (Dean et al., 2001; Fletcher et al., 2010) and have been extensively reviewed elsewhere (Al-Shawi, 2011). ABC importers play a major role in nutrient uptake, pathogenicity and virulence, making a focus on this diverse set of transporters ever more prevalent. ABC importers found in plants, prokaryotes and archaea are responsible for the transport of vital nutrients across lipid bilayers. In addition, many prokaryotic pathogens utilize ABC importers to circumvent the hosts innate immunes response, which makes this group of transporters of particular interest. All ABC transporters have a common basic architecture with two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). These domains assemble to form the basic unit of an ABC transporter. For ABC exporters, the TMD and NBD domains can be fused in multiple ways resulting in one-, two- or four-chain transporters, where the order of the domains may vary. For importers, the core TMD and NDB subunits are individual chains, which can assemble to form homo- or hetero-dimeric TMDs bound to typically homodimeric NBDs. The NBD is classified by a series of motifs, including the Walker A (P-loop), Walker B and ABC signature motif, which are common in, but not limited to ABC transporters (Higgins et al., 1986; Walker et al., 1982). These motifs, in conjunction with additional conserved NBD regions (H-loop/switch region, Q-loop), play a role in ATP binding (Schneider & Hunke, 1998). The binding and hydrolysis of ATP in the NBDs are thought to control the opening and closing of the TMDs. Unlike the NBD, the TMD sequence is considerably less conserved. For ABC importers, even the number of helices per TMD subunit can vary from 5 to 10, yielding a total of 10–۲۰ transmembrane helices per transporter (Davidson et al., 2008). TMDs of the ABC uptake systems contain the so-called EAA motif (L-loop), a cytoplasmic loop containing two short helices that couple conformational shifts of the NBDs to the TMDs (Saurin & Dassa, 1994, Saurin et al., 1994). Together, the TMDs and NBDs form a complex to make up the core unit of an ABC transporter. For most ABC importers, substrate is delivered to a core importer complex through a substrate-binding protein (SBP). SBPs bind to a vast array of substrates with affinities in the nanomolar to micromolar range. These proteins are located in the periplasm of gram-negative organisms or tethered to the membrane in gram-positive bacteria. The most recent discovery of ECF or energy coupling factor transporters has revealed a divergence in ABC importers. ECF transporters contain both NBDs and TMDs but do not have an additional SBP for substrate delivery. Instead, a membrane-embedded component of the ECF transporter binds substrate. The overall topology and mechanisms each type of importer uses to transport substrates emphasizes the diversity amongst ABC importers.