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

TitleStructural basis for a pH-sensitive calcium leak across membranes.
Publication TypeJournal Article
Year of Publication2014
AuthorsChang, Y, Bruni, R, Kloss, B, Assur, Z, Kloppmann, E, Rost, B, Hendrickson, WA, Liu, Q
Date Published2014 Jun 6
KeywordsBacillus subtilis, Bacterial Proteins, Calcium, Cell Membrane, Crystallography, X-Ray, Humans, Hydrogen-Ion Concentration, Membrane Proteins, Models, Molecular, Protein Structure, Secondary

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.

Alternate JournalScience
PubMed ID24904158
PubMed Central IDPMC4119810
Grant ListGM095315 / GM / NIGMS NIH HHS / United States
GM107462 / GM / NIGMS NIH HHS / United States
R01 GM107462 / GM / NIGMS NIH HHS / United States
U54 GM095315 / GM / NIGMS NIH HHS / United States