Massive expansions of the hexanucleotide in C9orf72 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 in vitro.

C9orf72中六核苷酸的大规模扩增是家族性肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）的主要遗传起源。当前的研究发现，该重复序列通过产生神经毒性物质并降低C9orf72蛋白水平而参与疾病过程。但是，C9orf72的功能研究进展缓慢。最近，由C9orf72，SMCR8和WDR41组成的稳定复合物已参与调节膜运输和大自噬。我们报道了C9orf72-SMCR8-WDR41复合物（CSW复合物）的低温电子显微镜（cryo-EM）结构，揭示了CSW复合物是异三聚体的二聚体。有趣的是，在C9orf72-SMCR8-WDR41的异三聚体中，C9orf72以与FLCN-FNIP2复合体相似的方式与SMCR8相互作用。不过，WDR41通过其N端β链和C端螺旋连接到SMCR8的DENN域，但不直接与C9orf72相互作用。值得注意的是，C9orf72-SMCR8复合物被证明可充当RAB8A和RAB11A的GAP体外。