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Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture

Nörpel, Julia, Cavadini, Simone, Schenk, Andreas D., Graff-Meyer, Alexandra, Hess, Daniel, Seebacher, Jan, Chao, Jeffrey A., Bhaskar, Varun·2021·PLOS Biology
DOI 10.1371/journal.pbio.3001344
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Abstract

A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G 4 C 2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G 4 C 2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.

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Cited by

Metadata

Authors
Nörpel, J., Cavadini, S., Schenk, A. D., Graff-Meyer, A., Hess, D., Seebacher, J., Chao, J. A., & Bhaskar, V.
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2021-07-23
Volume
19
Issue
7
Pages
e3001344
ISSN
1545-7885
DOI
10.1371/journal.pbio.3001344
Cited by
14
References
11
Language
en
Update notices
new_version (2021-08-04)
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • novartis research foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_182314)
  • snf-nccr rna & disease
  • synapsis foundation (2017 CDA 01)

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