Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.
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.
Hao
Bing
B
Howard Hughes Medical Institute, New York, New York 10021, USA.
Zheng
Ning
N
Schulman
Brenda A
BA
Wu
Geng
G
Miller
Julie J
JJ
Pagano
Michele
M
Pavletich
Nikola P
NP
D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D044842:Cullin Proteins / Q000737:chemistry / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D046912:Multiprotein Complexes; C479529:RBX1 protein, human; D044786:S-Phase Kinase-Associated Proteins; D044767:Ubiquitin-Protein Ligases; D018844:Cyclin-Dependent Kinases; C439298:p9(Cks1) protein, human