Cargando…
The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family
The RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834252/ https://www.ncbi.nlm.nih.gov/pubmed/36631489 http://dx.doi.org/10.1038/s41467-023-35871-z |
_version_ | 1784868421036408832 |
---|---|
author | Wang, Xiangyi S. Cotton, Thomas R. Trevelyan, Sarah J. Richardson, Lachlan W. Lee, Wei Ting Silke, John Lechtenberg, Bernhard C. |
author_facet | Wang, Xiangyi S. Cotton, Thomas R. Trevelyan, Sarah J. Richardson, Lachlan W. Lee, Wei Ting Silke, John Lechtenberg, Bernhard C. |
author_sort | Wang, Xiangyi S. |
collection | PubMed |
description | The RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this catalytic mechanism, we here structurally and biochemically characterise the two RBRs HOIL-1 and RNF216. Crystal structures of both enzymes in their RBR/E2-Ub/Ub transthiolation complexes capturing the first catalytic step, together with complementary functional experiments, reveal the defining features of the RBR catalytic mechanism. RBRs catalyse ubiquitination via a conserved transthiolation complex structure that enables efficient E2-to-RBR ubiquitin transfer. Our data also highlight a conserved RBR allosteric activation mechanism by distinct ubiquitin linkages that suggests RBRs employ a feed-forward mechanism. We finally identify that the HOIL-1 RING2 domain contains an unusual Zn2/Cys6 binuclear cluster that is required for catalytic activity and substrate ubiquitination. |
format | Online Article Text |
id | pubmed-9834252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98342522023-01-13 The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family Wang, Xiangyi S. Cotton, Thomas R. Trevelyan, Sarah J. Richardson, Lachlan W. Lee, Wei Ting Silke, John Lechtenberg, Bernhard C. Nat Commun Article The RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this catalytic mechanism, we here structurally and biochemically characterise the two RBRs HOIL-1 and RNF216. Crystal structures of both enzymes in their RBR/E2-Ub/Ub transthiolation complexes capturing the first catalytic step, together with complementary functional experiments, reveal the defining features of the RBR catalytic mechanism. RBRs catalyse ubiquitination via a conserved transthiolation complex structure that enables efficient E2-to-RBR ubiquitin transfer. Our data also highlight a conserved RBR allosteric activation mechanism by distinct ubiquitin linkages that suggests RBRs employ a feed-forward mechanism. We finally identify that the HOIL-1 RING2 domain contains an unusual Zn2/Cys6 binuclear cluster that is required for catalytic activity and substrate ubiquitination. Nature Publishing Group UK 2023-01-11 /pmc/articles/PMC9834252/ /pubmed/36631489 http://dx.doi.org/10.1038/s41467-023-35871-z 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 Wang, Xiangyi S. Cotton, Thomas R. Trevelyan, Sarah J. Richardson, Lachlan W. Lee, Wei Ting Silke, John Lechtenberg, Bernhard C. The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title | The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title_full | The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title_fullStr | The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title_full_unstemmed | The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title_short | The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family |
title_sort | unifying catalytic mechanism of the ring-between-ring e3 ubiquitin ligase family |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834252/ https://www.ncbi.nlm.nih.gov/pubmed/36631489 http://dx.doi.org/10.1038/s41467-023-35871-z |
work_keys_str_mv | AT wangxiangyis theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT cottonthomasr theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT trevelyansarahj theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT richardsonlachlanw theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT leeweiting theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT silkejohn theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT lechtenbergbernhardc theunifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT wangxiangyis unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT cottonthomasr unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT trevelyansarahj unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT richardsonlachlanw unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT leeweiting unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT silkejohn unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily AT lechtenbergbernhardc unifyingcatalyticmechanismoftheringbetweenringe3ubiquitinligasefamily |