Mitochondrial carriers in the cytoplasmic state have a common substrate binding site.
Mitochondrial carriers link biochemical pathways in the cytosol and mitochondrial matrix by transporting substrates across the inner mitochondrial membrane. Substrate recognition is specific for each carrier, but sequence similarities suggest the carriers have similar structures and mechanisms of substrate translocation. By considering conservation of amino acids, distance and chemical constraints, and by modeling family members on the known structure of the ADP/ATP translocase, we have identified a common substrate binding site. It explains substrate selectivity and proton coupling and provides a mechanistic link to carrier opening by substrate-induced perturbation of the salt bridges that seal the pathway to and from the mitochondrial matrix. It enables the substrate specificity of uncharacterized mitochondrial carriers to be predicted.
Robinson
Alan J
AJ
Dunn Human Nutrition Unit, Medical Research Council, Hills Road, Cambridge CB2 2XY, United Kingdom. ajr@mrc-dunn.cam.ac.uk
Kunji
Edmund R S
ER
D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D003593:Cytoplasm / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000737:chemistry; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry*; D024101:Mitochondrial Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D028061:Phosphate Transport Proteins / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D000071256:Uncoupling Protein 1; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases