SKP1 Connects Cell Cycle Regulators to the Ubiquitin Proteolysis Machinery through a Novel Motif, the F-Box

Abstract

We have identified the yeast and human homologs of the SKP1 gene as a suppressor of cdc4 mutants and as a cyclin F-binding protein. Skp1p indirectly binds cyclin A/Cdk2 through Skp2p, and directly binds Skp2p, cyclin F, and Cdc4p through a novel structural motif called the F-box. SKP1 is required for ubiquitin-mediated proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p, and provides a link between these molecules and the proteolysis machinery. A large number of proteins contain the F-box motif and are thereby implicated in the ubiquitin pathway. Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle.

The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin

“…Because these ligases are similar protein modules composed of Skp1, Cul A, and an F-box protein, they have been named SCFs. The F-box proteins (Fbps) are so-called because they contain an F-box motif (®rst identi®ed in Cyclin F) necessary for their interaction with Skp1 (Bai et al, 1996). In addition to the F-box, Fbps that are subunits of ubiquitin ligases contain other protein-protein interaction domains, such as WD-40 domains or leucine-rich repeats, that are involved in the recognition of speci®c substrates.…”

Two F‐box/WD‐repeat proteins Pop1 and Pop2 form hetero‐ and homo‐complexes together with cullin‐1 in the fission yeast SCF (Skp1‐Cullin‐1‐F‐box) ubiquitin ligase

“…Cdc34 is found to act in concert with a novel E3 (SCF) comprising a multiprotein complex composed of Cdc4, Cdc53 and Skp1 (Bai et al 1996;Mathias et al 1996;Willems et al 1996). Cdc4 contains two motifs, the F-box and WD-repeats (Neer et al 1994;Bai et al 1996). The F-box, consisting of around 40 amino acid residues, is found in a number of proteins from yeast to human, which has been proposed to be responsible for binding to another evolutionarily conserved protein Skp1.…”

Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

“…F-box proteins are the substrate-specific adaptor subunits of SCF E3 ubiquitin ligase complexes. [1][2][3][4][5][6] To identify the candidate substrates of the Fbxo45 ubiquitin ligase, we isolated Fbxo45 immunocomplexes by transient expression of HA-tagged Fbxo45 in human U87MG cell, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS data revealed known members of the atypical SCF complex, Fbxo45, Skp1 and MYCBP2.…”

“…[1][2][3][4][5][6] Previous studies have shown that in contrast to other F-box proteins that assemble SCF ubiquitin ligase complexes, Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (mycbinding protein 2). 7,8 Fbxo45 has been linked to the proteasomal degradation of a few targets including p73 9 and Munc13-1.…”