Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.

Autor: Nguyen DM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada., Rath DH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Devost D; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Pétrin D; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Rizk R; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Ji AX; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada., Narayanan N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Yong D; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Zhai A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Kuntz DA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Mian MUQ; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Pomroy NC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Keszei AFA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Benlekbir S; Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Mazhab-Jafari MT; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada., Rubinstein JL; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.; Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada., Hébert TE; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Privé GG; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 23; Vol. 121 (17), pp. e2315018121. Date of Electronic Publication: 2024 Apr 16.
DOI: 10.1073/pnas.2315018121
Abstrakt: 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 KCTD5 ) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3 NTD /Gβ 1 γ 2 assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5 BTB /CUL3 NTD and KCTD5 CTD /Gβγ moieties of the structure. CRL3 KCTD5 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 NTD /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.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze: MEDLINE
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