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. 2020 Aug;16(8):1542-1543.
doi: 10.1080/15548627.2020.1779473. Epub 2020 Jun 17.

The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases

Dan Tang  1 , Jingwen Sheng  1 , Liangting Xu  1 , Chuangye Yan  2 , Shiqian Qi  1
Affiliations

The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases

Dan Tang et al. Autophagy. 2020 Aug.

Abstract

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.

Keywords: ALS; DENN domain; FTD; RAB; autophagy; cryo-EM; dimer; longin domain; membrane.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Model of the CSW complex. (A) The overall structure of the CSW complex. The structure shows a two-fold symmetry. C9orf72, SMCR8, and WDR41 are colored in light blue, light green, and orange, respectively. The domains are denoted. The arginine finger is highlighted in red dashed lines. The dimer interface of the two protomers is denoted in blue dashed lines. (B) The proposed model of how the CSW complex promotes the fusion of endosomes: the CSW complex tethers two endosomes using WDR41, and promotes the fusion by activating RABs located on the surface of endosomes. C9orf72, SMCR8, and WDR41 are colored in blue, green, and yellow, respectively, while RABs are shown in dark blue. The arginine finger is highlighted as a dark pink line. The organization of domains is based on the structure in (A).
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References

    1. Tang D, Sheng J, Xu L, et al. Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a. Proc Natl Acad Sci U S A. 2020;117:9876–9883. - PMC - PubMed

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This work was supported by The National Key Research and Development Program of China grant 2017YFA0506300 (Q.S.) and NSFC grants 81671388 (Q. S.).

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