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Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase

G protein–coupled receptor (GPCR) signaling is precisely controlled to avoid overstimulation that results in detrimental consequences. Gβγ signaling is negatively regulated by a Cullin3 (Cul3)–dependent E3 ligase, KCTD5, which triggers ubiquitination and degradation of free Gβγ. Here, we report the...

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Autores principales: Jiang, Wentong, Wang, Wei, Kong, Yinfei, Zheng, Sanduo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348674/
https://www.ncbi.nlm.nih.gov/pubmed/37450587
http://dx.doi.org/10.1126/sciadv.adg8369
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author Jiang, Wentong
Wang, Wei
Kong, Yinfei
Zheng, Sanduo
author_facet Jiang, Wentong
Wang, Wei
Kong, Yinfei
Zheng, Sanduo
author_sort Jiang, Wentong
collection PubMed
description G protein–coupled receptor (GPCR) signaling is precisely controlled to avoid overstimulation that results in detrimental consequences. Gβγ signaling is negatively regulated by a Cullin3 (Cul3)–dependent E3 ligase, KCTD5, which triggers ubiquitination and degradation of free Gβγ. Here, we report the cryo–electron microscopy structures of the KCTD5-Gβγ fusion complex and the KCTD7-Cul3 complex. KCTD5 in pentameric form engages symmetrically with five copies of Gβγ through its C-terminal domain. The unique pentameric assembly of the KCTD5/Cul3 E3 ligase places the ubiquitin-conjugating enzyme (E2) and the modification sites of Gβγ in close proximity and allows simultaneous transfer of ubiquitin from E2 to five Gβγ subunits. Moreover, we show that ubiquitination of Gβγ by KCTD5 is important for fine-tuning cyclic adenosine 3´,5´-monophosphate signaling of GPCRs. Our studies provide unprecedented insights into mechanisms of substrate recognition by unusual pentameric E3 ligases and highlight the KCTD family as emerging regulators of GPCR signaling.
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spelling pubmed-103486742023-07-15 Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase Jiang, Wentong Wang, Wei Kong, Yinfei Zheng, Sanduo Sci Adv Biomedicine and Life Sciences G protein–coupled receptor (GPCR) signaling is precisely controlled to avoid overstimulation that results in detrimental consequences. Gβγ signaling is negatively regulated by a Cullin3 (Cul3)–dependent E3 ligase, KCTD5, which triggers ubiquitination and degradation of free Gβγ. Here, we report the cryo–electron microscopy structures of the KCTD5-Gβγ fusion complex and the KCTD7-Cul3 complex. KCTD5 in pentameric form engages symmetrically with five copies of Gβγ through its C-terminal domain. The unique pentameric assembly of the KCTD5/Cul3 E3 ligase places the ubiquitin-conjugating enzyme (E2) and the modification sites of Gβγ in close proximity and allows simultaneous transfer of ubiquitin from E2 to five Gβγ subunits. Moreover, we show that ubiquitination of Gβγ by KCTD5 is important for fine-tuning cyclic adenosine 3´,5´-monophosphate signaling of GPCRs. Our studies provide unprecedented insights into mechanisms of substrate recognition by unusual pentameric E3 ligases and highlight the KCTD family as emerging regulators of GPCR signaling. American Association for the Advancement of Science 2023-07-14 /pmc/articles/PMC10348674/ /pubmed/37450587 http://dx.doi.org/10.1126/sciadv.adg8369 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Jiang, Wentong
Wang, Wei
Kong, Yinfei
Zheng, Sanduo
Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title_full Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title_fullStr Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title_full_unstemmed Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title_short Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase
title_sort structural basis for the ubiquitination of g protein βγ subunits by kctd5/cullin3 e3 ligase
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348674/
https://www.ncbi.nlm.nih.gov/pubmed/37450587
http://dx.doi.org/10.1126/sciadv.adg8369
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