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Updated: Dec 23, 2025
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Combining X-Ray Crystallography with Small Angle X-Ray Scattering to Model Unstructured Regions of Nsa1 from S. Cerevisiae
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Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a.
Dan Tang1, Jingwen Sheng1, Liangting Xu1
1Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, 610041 Chengdu, China.
Summary
The C9ORF72-SMCR8-WDR41 complex structure reveals its dimeric assembly and identifies SMCR8
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- A hexanucleotide repeat expansion in C9ORF72 causes ALS and FTD.
- C9ORF72, SMCR8, and WDR41 regulate autophagy and act as Rab GEFs.
- The exact function of C9ORF72 remains elusive.
Purpose of the Study:
- To determine the cryo-EM structure of the human C9ORF72-SMCR8-WDR41 complex.
- To elucidate the molecular mechanisms underlying complex assembly and function.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) at 3.2 Å resolution.
- Structural comparison and sequence alignment.
- Biochemical analysis of SMCR8's Arg147 residue.
Main Results:
- The structure revealed a dimeric assembly of the C9ORF72-SMCR8-WDR41 heterotrimer.
- SMCR8 bridges C9ORF72 and WDR41 without direct interaction between the latter two.
- SMCR8's DENN domain and C9ORF72's C-terminal tail are crucial for dimerization.
- SMCR8's Arg147 residue is essential for the complex's GTPase activating protein (GAP) activity towards Rab8a and Rab11a.
Conclusions:
- The study provides the structural basis for C9ORF72-SMCR8-WDR41 complex assembly.
- The C9ORF72-SMCR8 complex exhibits GTPase activating protein (GAP) activity.
- This finding offers insights into the molecular mechanisms of C9ORF72-related neurodegenerative diseases.
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