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Publication Abstract from PubMed

G protein-coupled receptor (GPCR) signaling is precisely controlled to avoid overstimulation that results in detrimental consequences. Gbetagamma signaling is negatively regulated by a Cullin3 (Cul3)-dependent E3 ligase, KCTD5, which triggers ubiquitination and degradation of free Gbetagamma. Here, we report the cryo-electron microscopy structures of the KCTD5-Gbetagamma fusion complex and the KCTD7-Cul3 complex. KCTD5 in pentameric form engages symmetrically with five copies of Gbetagamma 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 Gbetagamma in close proximity and allows simultaneous transfer of ubiquitin from E2 to five Gbetagamma subunits. Moreover, we show that ubiquitination of Gbetagamma 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.

Structural basis for the ubiquitination of G protein betagamma subunits by KCTD5/Cullin3 E3 ligase.,Jiang W, Wang W, Kong Y, Zheng S Sci Adv. 2023 Jul 14;9(28):eadg8369. doi: 10.1126/sciadv.adg8369. Epub 2023 Jul , 14. PMID:37450587^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.