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Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair
G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B(12)-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by whi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356863/ https://www.ncbi.nlm.nih.gov/pubmed/37468522 http://dx.doi.org/10.1038/s41467-023-40077-4 |
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author | Mascarenhas, Romila Ruetz, Markus Gouda, Harsha Heitman, Natalie Yaw, Madeline Banerjee, Ruma |
author_facet | Mascarenhas, Romila Ruetz, Markus Gouda, Harsha Heitman, Natalie Yaw, Madeline Banerjee, Ruma |
author_sort | Mascarenhas, Romila |
collection | PubMed |
description | G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B(12)-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nano-assembly, which reveals a dramatic 180° rotation of the B(12) domain, exposing it to solvent. The complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the MMAA-MMUT interfaces we identify here. |
format | Online Article Text |
id | pubmed-10356863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103568632023-07-21 Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair Mascarenhas, Romila Ruetz, Markus Gouda, Harsha Heitman, Natalie Yaw, Madeline Banerjee, Ruma Nat Commun Article G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B(12)-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nano-assembly, which reveals a dramatic 180° rotation of the B(12) domain, exposing it to solvent. The complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the MMAA-MMUT interfaces we identify here. Nature Publishing Group UK 2023-07-19 /pmc/articles/PMC10356863/ /pubmed/37468522 http://dx.doi.org/10.1038/s41467-023-40077-4 Text en © The Author(s) 2023 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 Mascarenhas, Romila Ruetz, Markus Gouda, Harsha Heitman, Natalie Yaw, Madeline Banerjee, Ruma Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title_full | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title_fullStr | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title_full_unstemmed | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title_short | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair |
title_sort | architecture of the human g-protein-methylmalonyl-coa mutase nanoassembly for b(12) delivery and repair |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356863/ https://www.ncbi.nlm.nih.gov/pubmed/37468522 http://dx.doi.org/10.1038/s41467-023-40077-4 |
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