S-phase kinase-associated protein 2-Cyclin-dependent kinase regulatory subunit 1 protein-protein interface (Skp2-Cks1 interface)

The S-phase kinase-associated protein 2 (Skp2)-Cyclin-dependent kinase regulatory subunit 1 (Cks1) protein-protein interface is a pivotal regulatory node within the SCF^Skp2 E3 ubiquitin ligase complex (UniProt P63272, P61024). This interface is specifically required for the recruitment and polyubiquitination of the cyclin-dependent kinase inhibitor p27^Kip1, a key negative regulator of the G1/S phase transition (PubMed: 22854781). In various malignancies, including breast and prostate cancers, the overexpression of Skp2 and Cks1 facilitates the accelerated degradation of p27, driving oncogenic cell proliferation and poor clinical outcomes (PubMed: 23839240). Targeting this interface with small molecules aims to stabilize p27 levels and restore cell cycle control. Experimental inhibitors like Compound 67 and SZL-P1-41 have demonstrated the feasibility of disrupting this interaction to induce cell cycle arrest and apoptosis in cancer cells (PubMed: 22854781, 25201210). Unlike general proteasome inhibitors, targeting the Skp2-Cks1 interface offers a more selective strategy for modulating the ubiquitin-proteasome system in oncology. The structural basis of this interface involves the binding of Cks1 to the leucine-rich repeat domain of Skp2, creating a unique pocket for the phosphorylated Thr187 residue of p27 (PubMed: 16209941). Therapeutic development focuses on identifying drug-like molecules that can penetrate this shallow interface to prevent substrate binding without affecting other SCF complex functions.

Other names

Skp2-Cks1 complexSCF-Skp2-Cks1 interfacep27-binding pocket of Skp2-Cks1Skp2-Cks1-p27 interaction site

Small molecule inhibition of the protein-protein interaction between Skp2 and its cofactor Cks1, or the blocking of the substrate-binding pocket formed by the Skp2-Cks1 complex, which prevents the ubiquitination and subsequent proteasomal degradation of the tumor suppressor p27^Kip1.