期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 2, 页码 319-324出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1708677115
关键词
Skp1-FBXO31-cyclin D1 structure; ubiquitin system; cell cycle
资金
- National Institutes of Health [GM099948, GM113141]
- Connecticut Regenerative Medicine Research Fund [15-RMA-UCHC-04]
- National Center for Research Resources [S10 RR026680]
Ubiquitin-dependent proteolysis of cydin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1-Cul1-Rbx1-FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cydin D1 degradation. Previous studies have suggested that cydin 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 cydin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two beta-barrel motifs, whereas cydin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 beta-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cydin 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 cydin D1 protein turnover.
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