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Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination

How do the cullins, with conserved structures, accommodate substrate-binding proteins with distinct shapes and sizes? Cullin-RING E3 ubiquitin ligases facilitate ubiquitin transfer from E2 to the substrate, tagging the substrate for degradation. They contain substrate-binding, adaptor, cullin, and R...

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Autores principales: Liu, Jin, Nussinov, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220518/
https://www.ncbi.nlm.nih.gov/pubmed/21937436
http://dx.doi.org/10.1074/jbc.M111.277236
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author Liu, Jin
Nussinov, Ruth
author_facet Liu, Jin
Nussinov, Ruth
author_sort Liu, Jin
collection PubMed
description How do the cullins, with conserved structures, accommodate substrate-binding proteins with distinct shapes and sizes? Cullin-RING E3 ubiquitin ligases facilitate ubiquitin transfer from E2 to the substrate, tagging the substrate for degradation. They contain substrate-binding, adaptor, cullin, and Rbx proteins. Previously, we showed that substrate-binding and Rbx proteins are flexible. This allows shortening of the E2-substrate distance for initiation of ubiquitination or increasing the distance to accommodate the polyubiquitin chain. However, the role of the cullin remained unclear. Is cullin a rigid scaffold, or is it flexible and actively assists in the ubiquitin transfer reaction? Why are there different cullins, and how do these cullins specifically facilitate ubiquitination for different substrates? To answer these questions, we performed structural analysis and molecular dynamics simulations based on Cul1, Cul4A, and Cul5 crystal structures. Our results show that these three cullins are not rigid scaffolds but are flexible with conserved hinges in the N-terminal domain. However, the degrees of flexibilities are distinct among the different cullins. Of interest, Cul1 flexibility can also be changed by deletion of the long loop (which is absent in Cul4A) in the N-terminal domain, suggesting that the loop may have an allosteric functional role. In all three cases, these conformational changes increase the E2-substrate distance to a specific range to facilitate polyubiquitination, suggesting that rather than being inert scaffold proteins, cullins allosterically regulate ubiquitination.
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spelling pubmed-32205182011-11-23 Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination Liu, Jin Nussinov, Ruth J Biol Chem Protein Structure and Folding How do the cullins, with conserved structures, accommodate substrate-binding proteins with distinct shapes and sizes? Cullin-RING E3 ubiquitin ligases facilitate ubiquitin transfer from E2 to the substrate, tagging the substrate for degradation. They contain substrate-binding, adaptor, cullin, and Rbx proteins. Previously, we showed that substrate-binding and Rbx proteins are flexible. This allows shortening of the E2-substrate distance for initiation of ubiquitination or increasing the distance to accommodate the polyubiquitin chain. However, the role of the cullin remained unclear. Is cullin a rigid scaffold, or is it flexible and actively assists in the ubiquitin transfer reaction? Why are there different cullins, and how do these cullins specifically facilitate ubiquitination for different substrates? To answer these questions, we performed structural analysis and molecular dynamics simulations based on Cul1, Cul4A, and Cul5 crystal structures. Our results show that these three cullins are not rigid scaffolds but are flexible with conserved hinges in the N-terminal domain. However, the degrees of flexibilities are distinct among the different cullins. Of interest, Cul1 flexibility can also be changed by deletion of the long loop (which is absent in Cul4A) in the N-terminal domain, suggesting that the loop may have an allosteric functional role. In all three cases, these conformational changes increase the E2-substrate distance to a specific range to facilitate polyubiquitination, suggesting that rather than being inert scaffold proteins, cullins allosterically regulate ubiquitination. American Society for Biochemistry and Molecular Biology 2011-11-25 2011-09-20 /pmc/articles/PMC3220518/ /pubmed/21937436 http://dx.doi.org/10.1074/jbc.M111.277236 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Protein Structure and Folding
Liu, Jin
Nussinov, Ruth
Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title_full Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title_fullStr Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title_full_unstemmed Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title_short Flexible Cullins in Cullin-RING E3 Ligases Allosterically Regulate Ubiquitination
title_sort flexible cullins in cullin-ring e3 ligases allosterically regulate ubiquitination
topic Protein Structure and Folding
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220518/
https://www.ncbi.nlm.nih.gov/pubmed/21937436
http://dx.doi.org/10.1074/jbc.M111.277236
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