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Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusi...

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Autores principales: Plechanovová, Anna, Jaffray, Ellis, Tatham, Michael H., Naismith, James H., Hay, Ronald T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442243/
https://www.ncbi.nlm.nih.gov/pubmed/22842904
http://dx.doi.org/10.1038/nature11376
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author Plechanovová, Anna
Jaffray, Ellis
Tatham, Michael H.
Naismith, James H.
Hay, Ronald T.
author_facet Plechanovová, Anna
Jaffray, Ellis
Tatham, Michael H.
Naismith, James H.
Hay, Ronald T.
author_sort Plechanovová, Anna
collection PubMed
description Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING of RNF4 in complex with E2 (UbcH5a) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The C-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilise the consequent tetrahedral transition state intermediate.
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spelling pubmed-34422432013-03-06 Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis Plechanovová, Anna Jaffray, Ellis Tatham, Michael H. Naismith, James H. Hay, Ronald T. Nature Article Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING of RNF4 in complex with E2 (UbcH5a) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The C-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilise the consequent tetrahedral transition state intermediate. 2012-09-06 /pmc/articles/PMC3442243/ /pubmed/22842904 http://dx.doi.org/10.1038/nature11376 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Plechanovová, Anna
Jaffray, Ellis
Tatham, Michael H.
Naismith, James H.
Hay, Ronald T.
Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title_full Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title_fullStr Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title_full_unstemmed Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title_short Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
title_sort structure of a ring e3 ligase and ubiquitin-loaded e2 primed for catalysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442243/
https://www.ncbi.nlm.nih.gov/pubmed/22842904
http://dx.doi.org/10.1038/nature11376
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