Recombinant Human F-box/WD repeat-containing protein 7 (FBXW7) Protein

Function

Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:17434132, PubMed:22748924, PubMed:26976582, PubMed:28727686, PubMed:34741373, PubMed:35395208). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination (PubMed:17434132, PubMed:22748924, PubMed:26774286, PubMed:26976582, PubMed:28727686, PubMed:34741373). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, MLST8, RICTOR, and probably PSEN1 (PubMed:11565034, PubMed:11585921, PubMed:12354302, PubMed:14739463, PubMed:15103331, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:25775507, PubMed:25897075, PubMed:26976582, PubMed:28007894, PubMed:28727686, PubMed:29149593, PubMed:34102342). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286)

Subcellular Location

Nucleus, nucleolus

Disease Association

Developmental delay, hypotonia, and impaired language (DEDHIL) : An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, language difficulties, hypotonia, and gastrointestinal problems. Brain imaging shows variable structural abnormalities affecting the cerebellum, corpus collosum, and white matter. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Expressed in brain

Subunit

(Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region)

Pathway

Protein modification; protein ubiquitination

• Winston J.T. et al. A family of mammalian F-box proteins. — Curr. Biol. (1999)
• Moberg K.H. et al. Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. — Nature (2001)
• Strohmaier H. et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. — Nature (2001)
• Li J. et al. SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. — J. Neurochem. (2002)
• Bechtel S. et al. The full-ORF clone resource of the German cDNA consortium. — BMC Genomics (2007)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Wu G. et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. — Mol. Cell. Biol. (2001)