Structural basis for a pH-sensitive calcium leak across membranes

Allowing calcium to leak across a membrane Cells maintain a balance between calcium in the cytosol and calcium stored in organelles—too much stored calcium kills cells. Transmembrane Bax inhibitor motif (TMBIM) proteins form channels in organelle membranes that allow calcium to leak out. Chang et al. show that this calcium leak is pH-dependent. A bacterial homolog of TMBIM proteins converts between an open channel at low pH and a closed channel at high pH. Although the channel is open at low pH, calcium leakage is low because the inside of the channel remains at a neutral pH. Thus, at physiological pH, these channels will be in equilibrium between the open and closed states, so that excess calcium can leak through. Science, this issue p. 1131 pH sensing regulates calcium flow through a bacterial membrane channel that is a homolog of a human antiapoptotic protein. 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.