The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases
The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases
复制标题
C9orf72-SMCR8-WDR41 复合体是小型 GTPases 的 GAP
DOI：
10.1080/15548627.2020.1779473
复制
发表时间：
2020
期刊：
影响因子：
13.3
通讯作者：
Qi Shiqian
中科院分区：
文献类型：
--
作者：
Tang Dan;Sheng Jingwen;Xu Liangting;Yan Chuangye;Qi Shiqian
C9 orf 72中六核苷酸的大量扩增是家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的主要遗传起源。目前研究发现，该重复序列通过产生神经毒性物质和降低C9 orf 72蛋白水平参与疾病过程;然而，C9 orf 72的功能研究进展缓慢。最近，由C9 orf 72、SMCR 8和WDR 41组成的稳定复合物已涉及调节膜运输和巨自噬。我们报道了C9 orf 72-SMCR 8-WDR 41复合物（CSW复合物）的冷冻电镜（cryo-EM）结构，揭示了CSW复合物是异源三聚体的二聚体。有趣的是，在C9 orf 72-SMCR 8-WDR 41的异三聚体中，C9 orf 72以类似于FLCN-FNIP 2复合物的方式与SMCR 8相互作用。然而，WDR 41通过其N-末端β-链和C-末端螺旋连接到SMCR 8的DENN结构域，但不直接与C9 orf 72相互作用。值得注意的是，C9 orf 72-SMCR 8复合物被证明在体外充当RAB 8A和RAB 11 A的GAP。
Massive expansions of the hexanucleotide inC9orf72are the primary genetic origins of familial amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). Current studies have found that this repeat sequence participates in the disease process by producing neurotoxic substances and reducing the level of C9orf72 protein; however, the progress in the functional study of C9orf72 is slow. Recently, a stable complex, consisting of C9orf72, SMCR8, and WDR41, has been implicated in regulating membrane trafficking and macroautophagy. We reported the cryo-electron microscopy (cryo-EM) structure of the C9orf72-SMCR8-WDR41 complex (CSW complex), unveiling that the CSW complex is a dimer of heterotrimers. Intriguingly, in the heterotrimer of the C9orf72-SMCR8-WDR41, C9orf72 interacts with SMCR8 in a manner similar to the FLCN-FNIP2 complex. Nevertheless, WDR41 is connected to the DENN domain of SMCR8 through its N-terminal β-strand and C-terminal helix but does not directly interact with C9orf72. Notably, the C9orf72-SMCR8 complex was demonstrated to act as a GAP for RAB8A and RAB11Ain vitro.