Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)
Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)
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DOI：
10.1038/nsmb.3343
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发表时间：
2017-02-01
影响因子：
16.8
通讯作者：
Carpenter, Elisabeth P.
中科院分区：
文献类型：
--
作者：
Grieben, Mariana;Pike, Ashley C. W.;Carpenter, Elisabeth P.
多囊蛋白-1（PC1 或 PKD1）或多囊蛋白-2（PC2、PKD2 或 TRPP1）突变通过未知机制导致常染色体显性多囊肾病 (ADPKD)。在这里，我们展示了人类 PC2 的闭合构象结构，通过电子冷冻显微镜以 4.2 埃分辨率解析。该结构揭示了一种新颖的多囊蛋白特异性“多囊蛋白四角开口”（TOP）结构域，该结构域紧密结合到经典瞬时受体电位（TRP）通道结构的顶部。 TOP 域由类电压传感器域 (VSLD) 的两个扩展组成；它覆盖通道的内质网腔或细胞外表面，并包围孔过滤器上方的上前庭，而不阻塞离子传导路径。 TOP 结构域折叠在多囊蛋白中是保守的，包括 PC1 的同源通道样区域，并且是 ADPKD 相关错义变体簇的位点。 TOP 域亚基、孔和 VSLD 之间的广泛接触为通过物理和化学刺激进行调节提供了充足的范围。
Mutations in either polycystin-1 (PC1 or PKD1) or polycystin-2 (PC2, PKD2 or TRPP1) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms. Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-angstrom resolution. The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential (TRP) channel structure. The TOP domain is formed from two extensions to the voltage-sensor-like domain (VSLD); it covers the channel's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway. The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1, and is the site of a cluster of ADPKD-associated missense variants. Extensive contacts among the TOP-domain subunits, the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli.