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Structural basis for the ARF GAP activity and specificity of the C9orf72 complex
Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity to...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213707/ https://www.ncbi.nlm.nih.gov/pubmed/34145292 http://dx.doi.org/10.1038/s41467-021-24081-0 |
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author | Su, Ming-Yuan Fromm, Simon A. Remis, Jonathan Toso, Daniel B. Hurley, James H. |
author_facet | Su, Ming-Yuan Fromm, Simon A. Remis, Jonathan Toso, Daniel B. Hurley, James H. |
author_sort | Su, Ming-Yuan |
collection | PubMed |
description | Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF(3)(-) bound to C9orf72:SMCR8:WDR41. The SMCR8(longin) and C9orf72(longin) domains form the binding pocket for ARF1. One face of the C9orf72(longin) domain holds ARF1 in place, while the SMCR8(longin) positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway. |
format | Online Article Text |
id | pubmed-8213707 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82137072021-07-01 Structural basis for the ARF GAP activity and specificity of the C9orf72 complex Su, Ming-Yuan Fromm, Simon A. Remis, Jonathan Toso, Daniel B. Hurley, James H. Nat Commun Article Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF(3)(-) bound to C9orf72:SMCR8:WDR41. The SMCR8(longin) and C9orf72(longin) domains form the binding pocket for ARF1. One face of the C9orf72(longin) domain holds ARF1 in place, while the SMCR8(longin) positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway. Nature Publishing Group UK 2021-06-18 /pmc/articles/PMC8213707/ /pubmed/34145292 http://dx.doi.org/10.1038/s41467-021-24081-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Su, Ming-Yuan Fromm, Simon A. Remis, Jonathan Toso, Daniel B. Hurley, James H. Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title_full | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title_fullStr | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title_full_unstemmed | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title_short | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex |
title_sort | structural basis for the arf gap activity and specificity of the c9orf72 complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213707/ https://www.ncbi.nlm.nih.gov/pubmed/34145292 http://dx.doi.org/10.1038/s41467-021-24081-0 |
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