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Structure paper

TitleDynamic molecular architecture and substrate recruitment of cullin3-RING E3 ligase CRL3.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 2, Page 336-350, Year 2024
Publish dateFeb 8, 2024
AuthorsYuxia Hu / Zhao Zhang / Qiyu Mao / Xiang Zhang / Aihua Hao / Yu Xun / Yeda Wang / Lin Han / Wuqiang Zhan / Qianying Liu / Yue Yin / Chao Peng / Eva Marie Y Moresco / Zhenguo Chen / Bruce Beutler / Lei Sun /
PubMed AbstractPhosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. ...Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. Cellular levels of the regulatory p85α subunit are tightly controlled by regulated proteasomal degradation. In adipose tissue and growth plates, failure of K48-linked p85α ubiquitination causes diabetes, lipodystrophy and dwarfism in mice, as in humans with SHORT syndrome. Here we elucidated the structures of the key ubiquitin ligase complexes regulating p85α availability. Specificity is provided by the substrate receptor KBTBD2, which recruits p85α to the cullin3-RING E3 ubiquitin ligase (CRL3). CRL3 forms multimers, which disassemble into dimers upon substrate binding (CRL3-p85α) and/or neddylation by the activator NEDD8 (CRL3~N8), leading to p85α ubiquitination and degradation. Deactivation involves dissociation of NEDD8 mediated by the COP9 signalosome and displacement of KBTBD2 by the inhibitor CAND1. The hereby identified structural basis of p85α regulation opens the way to better understanding disturbances of glucose regulation, growth and cancer.
External linksNat Struct Mol Biol / PubMed:38332366
MethodsEM (single particle)
Resolution3.76 - 12.18 Å
Structure data

EMDB-34199, PDB-8gq6:
Cryo-EM Structure of the KBTBD2-CUL3-Rbx1 dimeric complex
Method: EM (single particle) / Resolution: 3.96 Å

EMDB-34449, PDB-8h33:
Cryo-EM Structure of the KBTBD2-Cul3-Rbx1 tetrameric complex
Method: EM (single particle) / Resolution: 7.86 Å

EMDB-34450, PDB-8h34:
Cryo-EM Structure of the KBTBD2-Cul3-Rbx1 hexameric complex
Method: EM (single particle) / Resolution: 7.99 Å

EMDB-34451, PDB-8h35:
Cryo-EM Structure of the KBTBD2-Cul3-Rbx1 octameric complex
Method: EM (single particle) / Resolution: 7.41 Å

EMDB-34452, PDB-8h36:
Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a dimeric complex
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-34453, PDB-8h37:
Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a tetrameric complex
Method: EM (single particle) / Resolution: 7.52 Å

EMDB-34454: local refinement of KBTBD2-p85a: KBTBD2-CRL3-p85a complex
Method: EM (single particle) / Resolution: 4.11 Å

EMDB-34455, PDB-8h38:
Cryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate) complex
Method: EM (single particle) / Resolution: 4.25 Å

EMDB-34456: local refinement of CSN1/2/4/5/6-CRL3/CTD-N8: KBTBD2-CRL3-CSN(mutate) complex
Method: EM (single particle) / Resolution: 4.84 Å

EMDB-34457: local refinement of CSN1/3/5/6/7/8: KBTBD2-CRL3-CSN(mutate) complex
Method: EM (single particle) / Resolution: 4.21 Å

EMDB-34458: local refinement of CSN5/6-CRL3/CTD-N8: KBTBD2-CRL3-CSN(mutate) complex
Method: EM (single particle) / Resolution: 4.29 Å

EMDB-34459: local refinement of KBTBD2-CRL3-CSN(mutate) complex
Method: EM (single particle) / Resolution: 4.25 Å

EMDB-34460: Cryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate,no CSN3/8) complex
Method: EM (single particle) / Resolution: 6.83 Å

EMDB-34461: Cryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate)-CSN(mutate,no CSN3/8) complex
Method: EM (single particle) / Resolution: 8.05 Å

EMDB-34462, PDB-8h3a:
Cryo-EM Structure of the KBTBD2-CRL3~N8(removed)-CSN complex
Method: EM (single particle) / Resolution: 7.51 Å

EMDB-34463: Cryo-EM Structure of the KBTBD2-CRL3~N8(removed)-CSN(no CSN3/8) complex
Method: EM (single particle) / Resolution: 7.15 Å

EMDB-34466: Cryo-EM Structure of the KBTBD2-CRL3-CSN(no CSN3/8) complex
Method: EM (single particle) / Resolution: 12.18 Å

EMDB-34467, PDB-8h3f:
Cryo-EM Structure of the KBTBD2-CRL3-CSN complex
Method: EM (single particle) / Resolution: 6.73 Å

EMDB-34473, PDB-8h3q:
Cryo-EM Structure of the CAND1-Cul3-Rbx1 complex
Method: EM (single particle) / Resolution: 3.76 Å

EMDB-34474, PDB-8h3r:
Cryo-EM Structure of the KBTBD2-CRL3~N8 dimeric complex
Method: EM (single particle) / Resolution: 6.36 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsLIGASE / complex

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