7z8b | pdb_00007z8b
Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation
Structural highlights
Disease[CUL7_HUMAN] Defects in CUL7 are the cause of 3M syndrome type 1 (3M1) [MIM:273750]. An autosomal recessive disorder characterized by severe pre- and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies.[1] Function[CUL7_HUMAN] Component of a probable SCF-like E3 ubiquitin-protein ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably plays a role in the degradation of proteins involved in endothelial proliferation and/or differentiation (By similarity). Seems not to promote polyubiquitination and proteasomal degradation of TP53. In vitro, complexes of CUL7 with either CUL9 or FBXW8 or TP53 contain E3 ubiquitin-protein ligase activity.[2] [3] Publication Abstract from PubMedMost cullin-RING ubiquitin ligases (CRLs) form homologous assemblies between a neddylated cullin-RING catalytic module and a variable substrate-binding receptor (for example, an F-box protein). However, the vertebrate-specific CRL7(FBXW8) is of interest because it eludes existing models, yet its constituent cullin CUL7 and F-box protein FBXW8 are essential for development, and CUL7 mutations cause 3M syndrome. In this study, cryo-EM and biochemical analyses reveal the CRL7(FBXW8) assembly. CUL7's exclusivity for FBXW8 among all F-box proteins is explained by its unique F-box-independent binding mode. In CRL7(FBXW8), the RBX1 (also known as ROC1) RING domain is constrained in an orientation incompatible with binding E2~NEDD8 or E2~ubiquitin intermediates. Accordingly, purified recombinant CRL7(FBXW8) lacks auto-neddylation and ubiquitination activities. Instead, our data indicate that CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination. The structure reveals a distinctive CRL-CRL partnership, and provides a framework for understanding CUL7 assemblies safeguarding human health. Structure of CRL7(FBXW8) reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation.,Hopf LVM, Baek K, Klugel M, von Gronau S, Xiong Y, Schulman BA Nat Struct Mol Biol. 2022 Aug 18. pii: 10.1038/s41594-022-00815-6. doi:, 10.1038/s41594-022-00815-6. PMID:35982156[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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