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Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5
UBR5 is a nuclear E3 ligase that ubiquitinates a vast range of substrates for proteasomal degradation. This HECT domain‐containing ubiquitin ligase has recently been identified as an important regulator of oncogenes, e.g., MYC, but little is known about its structure or mechanisms of substrate engag...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425842/ https://www.ncbi.nlm.nih.gov/pubmed/37409633 http://dx.doi.org/10.15252/embj.2022113348 |
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author | Hodáková, Zuzana Grishkovskaya, Irina Brunner, Hanna L Bolhuis, Derek L Belačić, Katarina Schleiffer, Alexander Kotisch, Harald Brown, Nicholas G Haselbach, David |
author_facet | Hodáková, Zuzana Grishkovskaya, Irina Brunner, Hanna L Bolhuis, Derek L Belačić, Katarina Schleiffer, Alexander Kotisch, Harald Brown, Nicholas G Haselbach, David |
author_sort | Hodáková, Zuzana |
collection | PubMed |
description | UBR5 is a nuclear E3 ligase that ubiquitinates a vast range of substrates for proteasomal degradation. This HECT domain‐containing ubiquitin ligase has recently been identified as an important regulator of oncogenes, e.g., MYC, but little is known about its structure or mechanisms of substrate engagement and ubiquitination. Here, we present the cryo‐EM structure of human UBR5, revealing an α‐solenoid scaffold with numerous protein–protein interacting motifs, assembled into an antiparallel dimer that adopts further oligomeric states. Using cryo‐EM processing tools, we observe the dynamic nature of the UBR5 catalytic domain, which we postulate is important for its enzymatic activity. We characterise the proteasomal nuclear import factor AKIRIN2 as an interacting protein and propose UBR5 as an efficient ubiquitin chain elongator. This preference for ubiquitinated substrates and several distinct domains for protein–protein interactions may explain how UBR5 is linked to several different signalling pathways and cancers. Together, our data expand on the limited knowledge of the structure and function of HECT E3 ligases. |
format | Online Article Text |
id | pubmed-10425842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104258422023-08-16 Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 Hodáková, Zuzana Grishkovskaya, Irina Brunner, Hanna L Bolhuis, Derek L Belačić, Katarina Schleiffer, Alexander Kotisch, Harald Brown, Nicholas G Haselbach, David EMBO J Articles UBR5 is a nuclear E3 ligase that ubiquitinates a vast range of substrates for proteasomal degradation. This HECT domain‐containing ubiquitin ligase has recently been identified as an important regulator of oncogenes, e.g., MYC, but little is known about its structure or mechanisms of substrate engagement and ubiquitination. Here, we present the cryo‐EM structure of human UBR5, revealing an α‐solenoid scaffold with numerous protein–protein interacting motifs, assembled into an antiparallel dimer that adopts further oligomeric states. Using cryo‐EM processing tools, we observe the dynamic nature of the UBR5 catalytic domain, which we postulate is important for its enzymatic activity. We characterise the proteasomal nuclear import factor AKIRIN2 as an interacting protein and propose UBR5 as an efficient ubiquitin chain elongator. This preference for ubiquitinated substrates and several distinct domains for protein–protein interactions may explain how UBR5 is linked to several different signalling pathways and cancers. Together, our data expand on the limited knowledge of the structure and function of HECT E3 ligases. John Wiley and Sons Inc. 2023-07-06 /pmc/articles/PMC10425842/ /pubmed/37409633 http://dx.doi.org/10.15252/embj.2022113348 Text en © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Hodáková, Zuzana Grishkovskaya, Irina Brunner, Hanna L Bolhuis, Derek L Belačić, Katarina Schleiffer, Alexander Kotisch, Harald Brown, Nicholas G Haselbach, David Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title | Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title_full | Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title_fullStr | Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title_full_unstemmed | Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title_short | Cryo‐EM structure of the chain‐elongating E3 ubiquitin ligase UBR5 |
title_sort | cryo‐em structure of the chain‐elongating e3 ubiquitin ligase ubr5 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425842/ https://www.ncbi.nlm.nih.gov/pubmed/37409633 http://dx.doi.org/10.15252/embj.2022113348 |
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