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Science. 2014 Jun 6;344(6188):1131-5. doi: 10.1126/science.1252043.

Structural basis for a pH-sensitive calcium leak across membranes.

Author information

1
New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA.
2
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
3
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.
4
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.
5
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.

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.

PMID:
24904158
PMCID:
PMC4119810
DOI:
10.1126/science.1252043
[Indexed for MEDLINE]
Free PMC Article

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