{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nguyen DM"],"funding":["Canadian Government | Canadian Institutes of Health Research","Canadian Government | Canadian Institutes of Health Research (CIHR)"],"pagination":["e2315018121"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11047111"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["121(17)"],"pubmed_abstract":["Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3<sup>KCTD5</sup>) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3<sup>NTD</sup>/Gβ<sub>1</sub>γ<sub>2</sub> assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5<sup>BTB</sup>/CUL3<sup>NTD</sup> and KCTD5<sup>CTD</sup>/Gβγ moieties of the structure. CRL3<sup>KCTD5</sup> engages the E3 ligase ARIH1 to ubiquitylate Gβγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gβ and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3<sup>NTD</sup>/Gβγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex."],"pmcid":["PMC11047111"],"funding_grant_id":["PJT-159687","PJT-191900"],"pubmed_authors":["Petrin D","Hebert TE","Nguyen DM","Devost D","Zhai A","Pomroy NC","Benlekbir S","Keszei AFA","Kuntz DA","Mazhab-Jafari MT","Rizk R","Rubinstein JL","Prive GG","Rath DH","Ji AX","Yong D","Narayanan N","Mian MUQ"],"additional_accession":[]},"is_claimable":false,"name":"Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.","description":"Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3<sup>KCTD5</sup>) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3<sup>NTD</sup>/Gβ<sub>1</sub>γ<sub>2</sub> assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5<sup>BTB</sup>/CUL3<sup>NTD</sup> and KCTD5<sup>CTD</sup>/Gβγ moieties of the structure. CRL3<sup>KCTD5</sup> engages the E3 ligase ARIH1 to ubiquitylate Gβγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gβ and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3<sup>NTD</sup>/Gβγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2026-07-01T03:08:27.702Z","creation":"2025-04-07T00:52:20.858Z"},"accession":"S-EPMC11047111","cross_references":{"pubmed":["38625940"],"doi":["10.1073/pnas.2315018121"]}}