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

G protein-coupled receptor (GPCR) signaling is precisely controlled to avoid overstimulation that results in detrimental consequences. G?? signaling is negatively regulated by a Cullin3 (Cul3)-dependent E3 ligase, KCTD5, which triggers ubiquitination and degradation of free G??. Here, we report the cryo-electron microscopy structures of the KCTD5-G?? fusion complex and the ...
KCTD7-Cul3 complex. KCTD5 in pentameric form engages symmetrically with five copies of G?? 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 G?? in close proximity and allows simultaneous transfer of ubiquitin from E2 to five G?? subunits. Moreover, we show that ubiquitination of G?? 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.
Mesh Terms:
Cryoelectron Microscopy, Cullin Proteins, GTP-Binding Proteins, Protein Binding, Ubiquitin-Protein Ligases, Ubiquitination
Sci Adv
Date: Jul. 14, 2023
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