title: The conserved substrate binding site of mitochondrial carriers.
abstract: Mitochondrial carriers transport nucleotides, co-factors and metabolic intermediates across the inner mitochondrial membrane permeability barrier. They belong to a family of transporters unique to eukaryotes and they differ in structure and transport mechanism from other secondary transporters. The main structural fold consists of a barrel of six transmembrane alpha-helices closed at the matrix side by a salt-bridge network at the bottom of the cavity. The significant sequence conservation in the mitochondrial carrier family suggests that specific recognition of substrates is coupled to a common mechanism of transport. We have identified a common substrate binding site comprising residues that are highly conserved and, as demonstrated by mutagenesis, are essential for function. The binding site explains substrate selectivity, ion coupling and the effects of the membrane potential on transport. The main contact points in the site are related by threefold symmetry like the common structural fold. The substrate is bound at the midpoint of the membrane and may function as a pivot point for the movements of the transmembrane alpha-helices as the carrier changes conformation. The trigger for the translocation event is likely to be the substrate-induced perturbation of the salt bridge network at the bottom of the cavity.
authors.affiliation: The Medical Research Council, Dunn Human Nutrition Unit, CB2 2XY, Cambridge, UK. ek@mrc-dunn.cam.ac.uk
authors.forename: Edmund R S
authors.initials: ER
authors.lastname: Kunji
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry* / Q000145:classification; D008969:Molecular Sequence Data; D010802:Phylogeny; D013379:Substrate Specificity; D015003:Yeasts / Q000737:chemistry*
chemical_list: D000226:Mitochondrial ADP, ATP Translocases