title: Structural basis for a pH-sensitive calcium leak across membranes.
abstract: Calcium homeostasis balances passive calcium leak and active calcium uptake. Human Bax inhibitor-1 (hBI-1) is an antiapoptotic protein that mediates a calcium leak and is representative of a highly conserved and widely distributed family, the transmembrane Bax inhibitor motif (TMBIM) proteins. Here, we present crystal structures of a bacterial homolog and characterize its calcium leak activity. The structure has a seven-transmembrane-helix fold that features two triple-helix sandwiches wrapped around a central C-terminal helix. Structures obtained in closed and open conformations are reversibly interconvertible by change of pH. A hydrogen-bonded, pKa (where Ka is the acid dissociation constant)-perturbed pair of conserved aspartate residues explains the pH dependence of this transition, and biochemical studies show that pH regulates calcium influx in proteoliposomes. Homology models for hBI-1 provide insights into TMBIM-mediated calcium leak and cytoprotective activity.
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Chang
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA.
authors.forename: Renato
authors.initials: R
authors.lastname: Bruni
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kloss
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Assur
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA. Department of Bioinformatics and Computational Biology, Fakultät für Informatik, Technische Universität München, Garching, Germany.
authors.forename: Edda
authors.initials: E
authors.lastname: Kloppmann
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA. Department of Bioinformatics and Computational Biology, Fakultät für Informatik, Technische Universität München, Garching, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Rost
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. New York Structural Biology Center, National Synchrotron Light Source (NSLS) X4, Brookhaven National Laboratory, Upton, NY 11973, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA. New York Structural Biology Center, National Synchrotron Light Source (NSLS) X4, Brookhaven National Laboratory, Upton, NY 11973, USA. qunliu@bnl.gov.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
mesh_terms: D001412:Bacillus subtilis / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D017433:Protein Structure, Secondary
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D002118:Calcium