Crystal structure of the epithelial calcium channel TRPV6.
Crystal structure of the epithelial calcium channel TRPV6.
复制标题
上皮钙通道TRPV6的晶体结构。
DOI：
10.1038/nature17975
复制
发表时间：
2016-06-23
期刊：
影响因子：
64.8
通讯作者：
Sobolevsky AI
中科院分区：
文献类型：
--
作者：
Saotome K;Singh AK;Yelshanskaya MV;Sobolevsky AI
钙稳态的精确调节对于许多生理功能至关重要。 Ca2+ 选择性 TRP 通道 TRPV5 和 TRPV6 作为上皮组织中的 Ca2+ 摄取通道，在钙稳态中发挥着重要作用。它们的组装和 Ca2+ 渗透的详细结构基础仍然不清楚。在这里，我们以 3.25 Å 的分辨率报告了大鼠 TRPV6 的晶体结构。与其他 TRP 通道相比，TRPV6 的整体架构揭示了共享和独特的功能。细胞内结构域参与广泛的相互作用，形成参与变构调节的细胞内“裙子”。在 K+ 通道样跨膜域中，Ca2+ 选择性是由选择性过滤器中的天冬氨酸侧链环与 Ca2+ 的直接配位决定的。基于晶体学鉴定的孔轴和细胞外前庭的阳离子结合位点，我们提出了 Ca2+ 渗透机制。我们的结果为理解上皮 Ca2+ 摄取的调节及其在病理生理学中的作用提供了结构基础。
Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca2+-selective TRP channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca2+ uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca2+ permeation remain obscure. Here, we report the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared to other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular “skirt” involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter. Based on crystallographically identified cation binding sites at the pore axis and extracellular vestibule, we propose a Ca2+ permeation mechanism. Our results provide a structural foundation to understand the regulation of epithelial Ca2+ uptake and its role in pathophysiology.