Abstract
Transporters are ubiquitous proteins mediating the translocation of solutes across cell membranes, a biological process involved in nutrition, signaling, neurotransmission, cell communication and drug uptake or efflux. Similarly to enzymes, most transporters have a single substrate binding-site and thus their activity follows Michaelis-Menten kinetics. Substrate binding elicits a series of structural changes, which produce a transporter conformer open toward the side opposite to the one from where the substrate was originally bound. This mechanism, involving alternate outward- and inward-facing transporter conformers, has gained significant support from structural, genetic, biochemical and biophysical approaches. Most transporters are specific for a given substrate or a group of substrates with similar chemical structure, but substrate specificity and/or affinity can vary dramatically, even among members of a transporter family that show high overall amino acid sequence and structural similarity. The current view is that transporter substrate affinity or specificity is determined by a small number of interactions a given solute can make within a specific binding site. However, genetic, biochemical and in silico modeling studies with the purine transporter UapA of the filamentous ascomycete Aspergillus nidulans have challenged this dogma. This review highlights results leading to a novel concept, stating that substrate specificity, but also transport kinetics and transporter turnover, are determined by subtle intramolecular interactions between a major substrate binding site and independent outward- or cytoplasmically-facing gating domains, analogous to those present in channels. This concept is supported by recent structural evidence from several, phylogenetically and functionally distinct transporter families. The significance of this concept is discussed in relationship to the role and potential exploitation of transporters in drug action.
Highlights
Transporters are ubiquitous proteins mediating the translocation of solutes across cell membranes, a biological process involved in nutrition, signaling, neurotransmission, cell communication and drug uptake or efflux
Nearly 70 bona fidae transporter crystal structures are known, of which less than 50 concern secondary active transporters, facilitators or antiporters, and only 4 of them are of eukaryotic origin
Bacterial transporter structures are used quite successfully to model human homologs, but this approach risks erroneous or overstated conclusions. This is so because bacterial transporters are usually smaller in length due to much shorter N- or C- terminal regions, or internal hydrophilic loops, which in eukaryotes have been shown to be extremely critical for transporter function, specificity, cellular sorting and turnover
Summary
Reviewed by: Andrei Adrian Tica, University of Medicine Craiova Romania, Romania Rajgopal Govindarajan, University of Georgia, Georgia. This review highlights results leading to a novel concept, stating that substrate specificity, and transport kinetics and transporter turnover, are determined by subtle intramolecular interactions between a major substrate binding site and independent outward- or cytoplasmically-facing gating domains, analogous to those present in channels This concept is supported by recent structural evidence from several, phylogenetically and functionally distinct transporter families. Transporters (or permeases or carriers) are polytopic transmembrane proteins that function as topological enzymes, that is, they catalyze the translocation of substrates from one side (Greek: topos) of the membrane to the other They comprise a single major substrate-binding site interacting with a single substrate molecule in each transport cycle. The TMS, which are linked by hydrophilic loops of different lengths www.frontiersin.org
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