Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase

Journal Article · Mon Jul 19 04:00:00 EDT 2010 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2005.09.003· OSTI ID:1008615

Hao, B; Zheng, N; Schulman, B A; Wu, G; Miller, J J; Pagano, M; Pavletich, N P ^[1]

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1. MSKCC

The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27{sup Kip1} plays a central role in cell cycle progression, and enhanced degradation of p27{sup Kip1} is associated with many common cancers. Proteolysis of p27{sup Kip1} is triggered by Thr187 phosphorylation, which leads to the binding of the SCF{sup Skp2} (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27{sup Kip1} ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27{sup Kip1} phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27{sup Kip1} binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27{sup Kip1} is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both. The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27{sup Kip1} to the SCF{sup Skp2}-Cks1 complex.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1008615
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Journal Issue: (1) ; 2005 Vol. 20; ISSN 1097-2765
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CELL CYCLE
CHAINS
CRYSTAL STRUCTURE
LIGASES
PHOSPHATES
PHOSPHORYLATION
PROTEINS
PROTEOLYSIS
SUBSTRATES