title: Calcium regulation of the human mitochondrial ATP-Mg/Pi carrier SLC25A24 uses a locking pin mechanism.
abstract: Mitochondrial ATP-Mg/Pi carriers import adenine nucleotides into the mitochondrial matrix and export phosphate to the cytosol. They are calcium-regulated to control the size of the matrix adenine nucleotide pool in response to cellular energetic demands. They consist of three domains: an N-terminal regulatory domain containing four calcium-binding EF-hands, a linker loop domain with an amphipathic α-helix and a C-terminal mitochondrial carrier domain for the transport of substrates. Here, we use thermostability assays to demonstrate that the carrier is regulated by calcium via a locking pin mechanism involving the amphipathic α-helix. When calcium levels in the intermembrane space are high, the N-terminus of the amphipathic α-helix is bound to a cleft in the regulatory domain, leading to substrate transport by the carrier domain. When calcium levels drop, the cleft closes, and the amphipathic α-helix is released to bind to the carrier domain via its C-terminus, locking the carrier in an inhibited state.
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.|School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Steven P D
authors.initials: SP
authors.lastname: Harborne
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Martin S
authors.initials: MS
authors.lastname: King
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.|Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Crichton
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Edmund R S
authors.initials: ER
authors.lastname: Kunji
mesh_terms: D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: C577335:ANAPC1 protein, human; C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; D002135:Calcium-Binding Proteins; D024101:Mitochondrial Proteins; C487500:SLC25A24 protein, human; D002118:Calcium