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Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER

Newly synthesized membrane proteins are queried by ubiquitin ligase complexes and triaged between degradative and nondegradative fates. The mechanisms that convert modest differences in substrate-ligase interactions into decisive outcomes of ubiquitination are not well understood. Here, we reconstit...

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Detalles Bibliográficos
Autores principales: Zhang, Zai-Rong, Bonifacino, Juan S., Hegde, Ramanujan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732389/
https://www.ncbi.nlm.nih.gov/pubmed/23890821
http://dx.doi.org/10.1016/j.cell.2013.06.038
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author Zhang, Zai-Rong
Bonifacino, Juan S.
Hegde, Ramanujan S.
author_facet Zhang, Zai-Rong
Bonifacino, Juan S.
Hegde, Ramanujan S.
author_sort Zhang, Zai-Rong
collection PubMed
description Newly synthesized membrane proteins are queried by ubiquitin ligase complexes and triaged between degradative and nondegradative fates. The mechanisms that convert modest differences in substrate-ligase interactions into decisive outcomes of ubiquitination are not well understood. Here, we reconstitute membrane protein recognition and ubiquitination in liposomes using purified components from a viral-mediated degradation pathway. We find that substrate-ligase interactions in the membrane directly influence processivity of ubiquitin attachment to modulate polyubiquitination. Unexpectedly, differential processivity alone could not explain the differential fates in cultured cells of degraded and nondegraded clients. Both computational and experimental analyses identified continuous deubiquitination as a prerequisite for maximal substrate discrimination. Deubiquitinases reduce polyubiquitin dwell times preferentially on clients that dissociate more rapidly from the ligase. This explains how small differences in substrate-ligase interaction can be amplified into larger differences in net degradation. These results provide a conceptual framework for substrate discrimination during membrane protein quality control.
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spelling pubmed-37323892013-08-05 Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER Zhang, Zai-Rong Bonifacino, Juan S. Hegde, Ramanujan S. Cell Article Newly synthesized membrane proteins are queried by ubiquitin ligase complexes and triaged between degradative and nondegradative fates. The mechanisms that convert modest differences in substrate-ligase interactions into decisive outcomes of ubiquitination are not well understood. Here, we reconstitute membrane protein recognition and ubiquitination in liposomes using purified components from a viral-mediated degradation pathway. We find that substrate-ligase interactions in the membrane directly influence processivity of ubiquitin attachment to modulate polyubiquitination. Unexpectedly, differential processivity alone could not explain the differential fates in cultured cells of degraded and nondegraded clients. Both computational and experimental analyses identified continuous deubiquitination as a prerequisite for maximal substrate discrimination. Deubiquitinases reduce polyubiquitin dwell times preferentially on clients that dissociate more rapidly from the ligase. This explains how small differences in substrate-ligase interaction can be amplified into larger differences in net degradation. These results provide a conceptual framework for substrate discrimination during membrane protein quality control. Cell Press 2013-08-01 /pmc/articles/PMC3732389/ /pubmed/23890821 http://dx.doi.org/10.1016/j.cell.2013.06.038 Text en © 2013 The Authors https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Zhang, Zai-Rong
Bonifacino, Juan S.
Hegde, Ramanujan S.
Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title_full Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title_fullStr Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title_full_unstemmed Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title_short Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER
title_sort deubiquitinases sharpen substrate discrimination during membrane protein degradation from the er
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732389/
https://www.ncbi.nlm.nih.gov/pubmed/23890821
http://dx.doi.org/10.1016/j.cell.2013.06.038
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