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

A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 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 re...

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Autores principales:	Julia Nörpel, Simone Cavadini, Andreas D Schenk, Alexandra Graff-Meyer, Daniel Hess, Jan Seebacher, Jeffrey A Chao, Varun Bhaskar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7177ef4f89824211b2898adb16149c96
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spelling	oai:doaj.org-article:7177ef4f89824211b2898adb16149c962021-12-02T19:54:22ZStructure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.1544-91731545-788510.1371/journal.pbio.3001344https://doaj.org/article/7177ef4f89824211b2898adb16149c962021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001344https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 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 G4C2 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.Julia NörpelSimone CavadiniAndreas D SchenkAlexandra Graff-MeyerDaniel HessJan SeebacherJeffrey A ChaoVarun BhaskarPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 7, p e3001344 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Julia Nörpel Simone Cavadini Andreas D Schenk Alexandra Graff-Meyer Daniel Hess Jan Seebacher Jeffrey A Chao Varun Bhaskar Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
description	A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 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 G4C2 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.
format	article
author	Julia Nörpel Simone Cavadini Andreas D Schenk Alexandra Graff-Meyer Daniel Hess Jan Seebacher Jeffrey A Chao Varun Bhaskar
author_facet	Julia Nörpel Simone Cavadini Andreas D Schenk Alexandra Graff-Meyer Daniel Hess Jan Seebacher Jeffrey A Chao Varun Bhaskar
author_sort	Julia Nörpel
title	Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
title_short	Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
title_full	Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
title_fullStr	Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
title_full_unstemmed	Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
title_sort	structure of the human c9orf72-smcr8 complex reveals a multivalent protein interaction architecture.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7177ef4f89824211b2898adb16149c96
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Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.

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