Structural basis for a pH-sensitive calcium leak across membranes

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacillus subtilis / metabolism*
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Calcium / metabolism*
  • Cell Membrane / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Hydrogen-Ion Concentration
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Protein Structure, Secondary

Substances

  • Bacterial Proteins
  • Membrane Proteins
  • Calcium

Associated data

  • PDB/4PGR
  • PDB/4PGS
  • PDB/4PGU
  • PDB/4PGV
  • PDB/4PGW