Mitochondrial carriers in the cytoplasmic state have a common substrate binding site

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 8; pp. 2617 - 2622
• Main Authors: Robinson, A.J, Kunji, E.R.S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.02.2006; National Acad Sciences
• Subjects: adenine nucleotide carriers; Adenine nucleotides; Adenosine diphosphate; Amino Acid Sequence; amino acid sequences; amino acid transporters; Amino acids; Binding Sites; Biochemistry; Biological Sciences; Biophysics; Carboxylates; Carrier Proteins - chemistry; Cytoplasm - metabolism; Functional groups; Guanosine Diphosphate - chemistry; Guanosine Triphosphate - chemistry; Humans; Ion Channels; keto acid transporters; Keto acids; membrane proteins; Membrane Proteins - chemistry; mitochondria; Mitochondrial ADP, ATP Translocases - chemistry; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Proteins; Models, Molecular; Molecular Sequence Data; Phosphate Transport Proteins - chemistry; Phosphates; Saccharomyces cerevisiae; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Substrate specificity; Substrates; Translocation; transport proteins; Uncoupling Protein 1; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509994103

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.