Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, NY 10032, USA.
Sci Adv. 2018 Aug 15;4(8):eaau6088. doi: 10.1126/sciadv.aau6088. eCollection 2018 Aug.
Calcium (Ca) plays a major role in numerous physiological processes. Ca homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)-mediated Ca-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient receptor potential vanilloid subfamily member 6) inactivated by CaM. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM carboxyl-terminal lobe plugs the channel through a unique cation-π interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the pore's intracellular entrance. We propose a mechanism of CaM-mediated Ca-induced inactivation that can be explored for therapeutic design.
钙 (Ca) 在许多生理过程中发挥着重要作用。Ca 稳态由离子通道严格控制，其异常调节导致包括癌症在内的各种疾病。钙调蛋白 (CaM) 介导的 Ca 诱导失活是一种离子通道调节机制，可保护细胞免受 Ca 过载的毒性影响。我们使用冷冻电子显微镜捕获了由 CaM 失活的上皮钙通道 TRPV6（瞬时受体电位香草素亚家族成员 6）。TRPV6-CaM 复合物表现出 1:1 的化学计量比；一个 TRPV6 四聚体结合两个 CaM 结构域，它们采用独特的头到尾排列。CaM 羧基末端结构域通过独特的阳离子-π 相互作用将通道堵塞，将赖氨酸 K115 的侧链插入到腔内入口处四色色氨酸笼中。我们提出了一种 CaM 介导的 Ca 诱导失活的机制，可用于治疗设计。
