Structural basis of the Cks1-dependent recognition of p27 Kip1 by the SCF Skp2 ubiquitin ligase Journal Article
| Authors: | Hao, B.; Zheng, N.; Schulman, B. A.; Wu, G.; Miller, J. J.; Pagano, M.; Pavletich, N. P. |
| Article Title: | Structural basis of the Cks1-dependent recognition of p27 Kip1 by the SCF Skp2 ubiquitin ligase |
| Abstract: | 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. Copyright ©2005 by Elsevier Inc. |
| Keywords: | unclassified drug; protein domain; neoplasms; cell cycle proteins; cell cycle; amino acid substitution; ubiquitin protein ligase; carboxy terminal sequence; protein degradation; protein; protein binding; phosphorylation; cyclin dependent kinase inhibitor 1b; molecular recognition; carrier proteins; binding protein; binding site; crystal structure; crystallography, x-ray; multiprotein complexes; protein structure; structure analysis; enzyme specificity; cyclin-dependent kinases; enzyme binding; protein structure, quaternary; ubiquitin-protein ligases; protein structure, secondary; s phase kinase associated protein 2; s-phase kinase-associated proteins; cullin proteins; enzyme variant; protein csk1; protein scf skp2 |
| Journal Title: | Molecular Cell |
| Volume: | 20 |
| Issue: | 1 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2005-10-07 |
| Start Page: | 9 |
| End Page: | 19 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2005.09.003 |
| PUBMED: | 16209941 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 111" - "Export Date: 24 October 2012" - "CODEN: MOCEF" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work