SKP2

Description

The SKP2 (S-phase kinase associated protein 2) is a protein-coding gene located on chromosome 5.

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

== Structure and function == Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-140 position and the C-terminal region forming a concave surface consisting of ten leucine-rich repeats (LRRs). The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which often—but not always—recognize substrates in a phosphorylation-dependent manner. In this SCF complex, Skp2 acts as the substrate recognition factor.

=== F-box Domain === The F-box proteins are divided into three classes: Fbxws containing WD40 repeat domains, Fbxls containing leucine-rich repeats, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxls class. In addition to an F-box, this protein contains 10 tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms. After the tenth LRR, the ~30-residue C-terminal tail turns back towards the first LRR, forming what has been referred to as a ‘safety-belt’ that might aid to pin down substrates into the concave surface formed by the LRRs. Skp2 forms a stable complex with the cyclin A-CDK2 S-phase kinase.

SKP2 is a crucial component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex, which plays a vital role in controlling the degradation of proteins involved in cell cycle progression, signal transduction, and transcription. SKP2 specifically recognizes phosphorylated CDKN1B/p27kip, contributing to the regulation of the G1/S transition. The degradation of CDKN1B/p27kip also requires the participation of CKS1. SKP2 recognizes a diverse range of target proteins, including ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, YTHDF2, and potentially MYC, TOB1, and TAL1. Degradation of TAL1 further necessitates the involvement of STUB1. SKP2 interacts with CDKN1A in conjunction with CCNE1 or CCNE2 and CDK2. It promotes the ubiquitination and subsequent destruction of CDH1 in a CK1-dependent manner, thus regulating cell migration. Upon phosphorylation in response to DNA damage, SKP2 mediates 'Lys-63'-linked ubiquitination of NBN, facilitating the recruitment of ATM to DNA damage sites and DNA repair through homologous recombination.

SKP2 is also known as FBL1, FBXL1, FLB1, p45.

Associated Diseases

WES Whole Exome Sequencing