C9orf72-SMCR8-WDR41 复合物是小 GTPases 的 GAP。
The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases.
机构信息
Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University , Chengdu, China.
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing, China.
出版信息
Autophagy. 2020 Aug;16(8):1542-1543. doi: 10.1080/15548627.2020.1779473. Epub 2020 Jun 17.
Massive expansions of the hexanucleotide in are 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 RAB11A .
重复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。目前的研究发现，该重复序列通过产生神经毒性物质和降低 C9orf72 蛋白水平参与疾病过程；然而，C9orf72 的功能研究进展缓慢。最近，由 C9orf72、SMCR8 和 WDR41 组成的稳定复合物被牵连到调节膜运输和巨自噬中。我们报道了 C9orf72-SMCR8-WDR41 复合物（CSW 复合物）的冷冻电子显微镜（cryo-EM）结构，揭示了 CSW 复合物是三聚体异源二聚体的二聚体。有趣的是，在 C9orf72-SMCR8-WDR41 的三聚体中，C9orf72 与 SMCR8 的相互作用方式类似于 FLCN-FNIP2 复合物。然而，WDR41 通过其 N 端β-链和 C 端螺旋与 SMCR8 的 DENN 结构域相连，但不直接与 C9orf72 相互作用。值得注意的是，C9orf72-SMCR8 复合物被证明是 RAB8A 和 RAB11A 的 GAP。
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