title: Fbw7 dimerization determines the specificity and robustness of substrate degradation.
abstract: The Fbw7 tumor suppressor targets a broad network of proteins for ubiquitylation. Here we show critical functions for Fbw7 dimerization in regulating the specificity and robustness of degradation. Dimerization enables Fbw7 to target substrates through concerted binding to two suboptimal and independent recognition sites. Accordingly, an endogenous dimerization-deficient Fbw7 mutation stabilizes suboptimal substrates. Dimerization increases Fbw7's robustness by preserving its function in the setting of mutations that disable Fbw7 monomers, thereby buffering against pathogenic mutations. Finally, dimerization regulates Fbw7 stability, and this likely involves Fbw7 trans-autoubiquitylation. Our study reveals novel functions of Fbw7 dimerization and an unanticipated complexity in substrate degradation.
authors.affiliation: Clinical Research Division.
authors.forename: Markus
authors.initials: M
authors.lastname: Welcker
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Larimore
authors.forename: Jherek
authors.initials: J
authors.lastname: Swanger
authors.forename: Maria T
authors.initials: MT
authors.lastname: Bengoechea-Alonso
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Grim
authors.forename: Johan
authors.initials: J
authors.lastname: Ericsson
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Clurman
mesh_terms: D020816:Amino Acid Motifs; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D045325:HCT116 Cells; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D055550:Protein Stability; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases
keywords: Fbw7; SCF; cyclin E; phosphodegron