Structural Basis of the Cks1-Dependent Recognition of P27Kip1 by the SCF skp2 Ubiquitin Ligase

Journal Article · Sat Jan 01 04:00:00 EST 2005 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2005.09.003· OSTI ID:913743

Hao, B; Zheng, N; Schulman, B; Wu, G; Miller, J; Pagano, M; Pavletich, N

The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27(Kip1) plays a central role in cell cycle progression, and enhanced degradation of p27(Kip1) is associated with many common cancers. Proteolysis of p27(Kip1) is triggered by Thr187 phosphorylation, which leads to the binding of the SCF(Skp2) (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27(Kip1) ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27(Kip1) phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27(Kip1) binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27(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(Kip1) to the SCF(Skp2)-Cks1 complex.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 913743
• Report Number(s): BNL--78311-2007-JA
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Journal Issue: 1 Vol. 20
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CELL CYCLE
CHAINS
CRYSTAL STRUCTURE
LIGASES
PHOSPHATES
PHOSPHORYLATION
PROTEINS
PROTEOLYSIS
SUBSTRATES
national synchrotron light source