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 anti-apoptotic protein that mediates a calcium leak and is representative of 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 inter-convertible by change of pH. A hydrogen-bonded, pKa-perturbed pair of conserved aspartate residues explains the pH dependence of this equilibrium, 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.

Bax Inhibitor-1 Is Likely a pH-Sensitive Calcium Leak Channel, Not a H + /Ca 2+ Exchanger

“…Chang and co-workers provide structural evidence that a bacterial homolog of Bax inhibitor-1 (BI-1) mediates Ca 2+ fl ux across proteoliposome membranes at neutral pH and is inhibited by both acidic and basic pH (1). This supports earlier conclusions drawn from in vitro experiments that BI-1 plays a critical role in Ca 2+ fl uxes across ER membranes (2,3).…”

Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis

“…S1). Flexible intervening molecular layers in a crystalline lattice are not unprecedented as this phenomenon was also observed in the crystal lattice of the calcium channel YetJ (PDB ID code 4PGW) (43) and outer membrane porin OmpG (PDB ID code 2IWV) (44). Furthermore, the high variability of the c-axis of unit cell by as much as 5-10% in different PafE ΔN14ΔC21 crystals is another indication that crystallographic packing in the c direction contained flexible elements (SI Appendix, Table S5).…”

Context-Dependent GluN2B-Selective Inhibitors of NMDA Receptor Function Are Neuroprotective with Minimal Side Effects

“…The juxtaposition of ionizable side chains by tertiary protein structure has been suggested to shift intra-protein pKa values (Harris and Turner 2002; Jasti et al, 2007; Ritschel et al, 2009; Bombarda and Ullmann 2010; Sussman et al, 2013), creating a carboxylate-based pH sensor for ligand binding within the amino terminal domain that docking studies suggest directly interacts with 93-31. Interestingly, an interacting carboxylate pair has recently been suggested to form the pH sensor of a Ca 2+ leak channel (Chang et al, 2014). While the Ca 2+ leak channel dicarboxylate pair does not form the classic reciprocal hydrogen bonding of a carboxylic acid dimer, it nonetheless alternates between multiple states with varying pH, including protonation of both side-chains.…”