The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2.
The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2.
复制标题
DOI：
10.1016/j.jbc.2023.104674
复制
发表时间：
2023-05
影响因子：
4.8
通讯作者：
Yu, Yong
中科院分区：
文献类型：
--
作者：
Wang, Yan;Wang, Zhifei;Pavel, Mahmud Arif;Ng, Courtney;Kashyap, Parul;Li, Bin;Morais, Tiago D. C.;Ulloa, Gabriella A.;Yu, Yong
常染色体显性多囊肾病是由PKD1或PKD2基因突变引起的。后者编码多囊蛋白-2 (PC2，也称为TRPP2)，是瞬时受体电位离子通道家族的成员。尽管PKD2的致病性突变大多数是截断变异，但也有许多点突变，这些点突变导致蛋白质序列的微小变化，但PC2的体内功能却发生了巨大变化。这些突变如何影响PC2离子通道功能在很大程度上是未知的。在这项研究中，我们系统地测试了31个点突变对爪蟾卵母细胞中表达的功能获得型PC2突变体PC2_F604P离子通道活性的影响。结果表明，PC2_F604P通道功能的关键是跨膜结构域和通道孔区域的所有突变，以及多囊毒素结构域细胞外四方开口的大部分突变。相比之下，在非洲爪蟾卵母细胞中，多囊蛋白结构域四边形开口的其他突变和c端尾部的大多数突变对通道功能的影响很小或没有影响。为了理解这些影响的机制，我们根据PC2的低温电镜结构讨论了这些突变可能造成的构象后果。这些结果有助于深入了解PC2离子通道的结构和功能以及这些突变引起的发病机制。
Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes. The latter encodes polycystin-2 (PC2, also known as TRPP2), a member of the transient receptor potential ion channel family. Despite most pathogenic mutations in PKD2 being truncation variants, there are also many point mutations, which cause small changes in protein sequences but dramatic changes in the in vivo function of PC2. How these mutations affect PC2 ion channel function is largely unknown. In this study, we systematically tested the effects of 31 point mutations on the ion channel activity of a gain-of-function PC2 mutant, PC2_F604P, expressed in Xenopus oocytes. The results show that all mutations in the transmembrane domains and channel pore region, and most mutations in the extracellular tetragonal opening for polycystins domain, are critical for PC2_F604P channel function. In contrast, the other mutations in the tetragonal opening for polycystins domain and most mutations in the C-terminal tail cause mild or no effects on channel function as assessed in Xenopus oocytes. To understand the mechanism of these effects, we have discussed possible conformational consequences of these mutations based on the cryo-EM structures of PC2. The results help gain insight into the structure and function of the PC2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.
登录
查看更多内容
影响因子：
10.5
作者：
Harris PC;Torres VE
通讯作者：
Torres VE
影响因子：
56.9
作者：
Mochizuki, T;Wu, GQ;Somlo, S
通讯作者：
Somlo, S
影响因子：
8
作者：
Allen, Mark D.;Qamar, Seema;Vadivelu, Murali K.;Sandford, Richard N.;Bycroft, Mark
通讯作者：
Bycroft, Mark
影响因子：
11.4
作者：
Bai, Chang-Xi;Kim, Sehyun;Tsiokas, Leonidas
通讯作者：
Tsiokas, Leonidas
DOI：
10.1007/978-1-4939-0928-5_16
发表时间：
2014-01-01
期刊：
CYTOKINE BIOASSAYS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Pavel, Mahmud Arif;Lam, Clarissa;Yu, Yong
通讯作者：
Yu, Yong