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Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):319-324. doi: 10.1073/pnas.1708677115. Epub 2017 Dec 26.

Structural basis of the phosphorylation-independent recognition of cyclin D1 by the SCFFBXO31 ubiquitin ligase.

Author information

1
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030.
2
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309.
3
Biomolecular Resource Facility, University of Texas Medical Branch, Galveston, TX 77555.
4
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030; bhao@uchc.edu.

Abstract

Ubiquitin-dependent proteolysis of cyclin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1-Cul1-Rbx1-FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cyclin D1 degradation. Previous studies have suggested that cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and subsequent proteolysis in the cytoplasm. Here we present the crystal structures of the Skp1-FBXO31 complex alone and bound to a phosphorylated cyclin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two β-barrel motifs, whereas cyclin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 β-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cyclin D1 in a phosphorylation-independent manner. Our findings provide a conceptual framework for understanding the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover.

KEYWORDS:

Skp1–FBXO31–cyclin D1 structure; cell cycle; ubiquitin system

PMID:
29279382
PMCID:
PMC5777030
DOI:
10.1073/pnas.1708677115
[Indexed for MEDLINE]
Free PMC Article

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