A family of mammalian F-box proteins.
Ubiquitin-mediated destruction of regulatory proteins is a frequent means of controlling progression through signaling pathways [1]. F-box proteins [2] are components of modular E3 ubiquitin protein ligases called SCFs, which function in phosphorylation-dependent ubiquitination ([3] [4] [5], reviewed in [6] [7]). F-box proteins contain a carboxy-terminal domain that interacts with substrates and a 42-48 amino-acid F-box motif which binds to the protein Skp1 [2] [3] [4]. Skp1 binding links the F-box protein with a core ubiquitin ligase composed of the proteins Cdc53/Cul1, Rbx1 (also called Hrt1 and Roc1) and the E2 ubiquitin-conjugating enzyme Cdc34 [8] [9] [10] [11]. The genomes of the budding yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans contain, respectively, 16 and more than 60 F-box proteins [2] [7]; in S. cerevisiae, the F-box proteins Cdc4, Grr1 and Met30 target cyclin-dependent kinase inhibitors, G1 cyclins and transcriptional regulators for ubiquitination ([3] [4] [5] [8] [10], reviewed in [6] [7]). Only four mammalian F-box proteins (Cyclin F, Skp1, beta-TRCP and NFB42) have been identified so far [2] [12]. Here, we report the identification of a family of 33 novel mammalian F-box proteins. The large number of these proteins in mammals suggests that the SCF system controls a correspondingly large number of regulatory pathways in vertebrates. Four of these proteins contain a novel conserved motif, the F-box-associated (FBA) domain, which may represent a new protein-protein interaction motif. The identification of these genes will help uncover pathways controlled by ubiquitin-mediated proteolysis in mammals.
Winston
J T
JT
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA.
Koepp
D M
DM
Zhu
C
C
Elledge
S J
SJ
Harper
J W
JW
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000378:metabolism; D010802:Phylogeny; D011506:Proteins / Q000737:chemistry* / Q000145:classification* / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques; D014452:Ubiquitins / Q000378:metabolism
D011506:Proteins; D014452:Ubiquitins; D044843:SKP Cullin F-Box Protein Ligases; D010453:Peptide Synthases