Chang Yanqi, Bruni Renato, Kloss Brian, Assur Zahra, Kloppmann Edda, Rost Burkhard, Hendrickson Wayne A, Liu Qun
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.
Science. 2014 Jun 6;344(6188):1131-5. doi: 10.1126/science.1252043.
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.
钙稳态平衡了被动钙泄漏和主动钙摄取。人类 Bax 抑制剂 -1（hBI-1）是一种抗凋亡蛋白，介导钙泄漏，代表了一个高度保守且广泛分布的家族——跨膜 Bax 抑制剂基序（TMBIM）蛋白家族。在此，我们展示了一种细菌同源物的晶体结构，并对其钙泄漏活性进行了表征。该结构具有七跨膜螺旋折叠，其特征是两个三重螺旋三明治结构围绕着一个中央 C 末端螺旋。在封闭和开放构象中获得的结构可通过改变 pH 值可逆地相互转换。一对通过氢键结合、pKa（其中 Ka 是酸解离常数）受扰动的保守天冬氨酸残基解释了这种转变对 pH 的依赖性，生化研究表明 pH 调节蛋白脂质体中的钙内流。hBI-1 的同源模型为 TMBIM 介导的钙泄漏和细胞保护活性提供了见解。
