S-phase kinase-associated protein 2 – S-phase kinase-associated protein 1 interface (Skp2–Skp1 interface)

The Skp2–Skp1 interface is a critical protein-protein interaction site within the SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase complex (Wu et al., 2012, Nature). Skp2 serves as the substrate-recognition component (F-box protein), while Skp1 acts as an adapter protein that bridges Skp2 to the Cullin-1 scaffold (UniProt Q13309). This interaction is essential for the assembly of the functional SCF-Skp2 complex, which mediates the ubiquitination and subsequent proteasomal degradation of key cell cycle regulators, most notably the cyclin-dependent kinase inhibitor p27 (Kip1) (Chan et al., 2013, Cell). In many human cancers, Skp2 is overexpressed, leading to the premature degradation of p27 and promoting uncontrolled cell proliferation and tumor progression (Frescas & Pagano, 2008, Nature Reviews Cancer). Consequently, the Skp2–Skp1 interface has emerged as a promising therapeutic target for the development of small-molecule inhibitors. These inhibitors, such as the compounds C1 and SZL-P1, disrupt the recruitment of Skp2 to the SCF complex, thereby stabilizing p27 levels and inducing cell cycle arrest and apoptosis in cancer cells (Wu et al., 2012; Chen et al., 2015, Oncogene). Targeting this specific interface offers a strategy to restore the tumor-suppressive functions of p27 without broadly inhibiting the entire proteasome system.

Other names

Skp2-Skp1 complex interfaceSCF-Skp2 interfaceFBXL1-Skp1 interfaceS-phase kinase-associated protein 2 – S-phase kinase-associated protein 1 complex

Inhibition of protein-protein interaction between Skp2 and Skp1, preventing the assembly of the SCF-Skp2 E3 ligase complex and stabilizing substrate proteins like p27.