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Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination.

SCF ubiquitin ligases recruit substrates for degradation via F box protein adaptor subunits. WD40 repeat F box proteins, such as Cdc4 and beta-TrCP, contain a conserved dimerization motif called the D domain. Here, we report that the D domain protomers of yeast Cdc4 and human beta-TrCP form a superhelical homotypic dimer. Disruption of the D domain compromises the activity of yeast SCF(Cdc4) toward the CDK inhibitor Sic1 and other substrates. SCF(Cdc4) dimerization has little effect on the affinity for Sic1 but markedly stimulates ubiquitin conjugation. A model of the dimeric holo-SCF(Cdc4) complex based on small-angle X-ray scatter measurements reveals a suprafacial configuration, in which substrate-binding sites and E2 catalytic sites lie in the same plane with a separation of 64 A within and 102 A between each SCF monomer. This spatial variability may accommodate diverse acceptor lysine geometries in both substrates and the elongating ubiquitin chain and thereby increase catalytic efficiency.

Pubmed ID: 17574027


  • Tang X
  • Orlicky S
  • Lin Z
  • Willems A
  • Neculai D
  • Ceccarelli D
  • Mercurio F
  • Shilton BH
  • Sicheri F
  • Tyers M



Publication Data

June 15, 2007

Associated Grants

  • Agency: NCRR NIH HHS, Id: RR-08630

Mesh Terms

  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain
  • Cell Cycle Proteins
  • Dimerization
  • F-Box Proteins
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • SKP Cullin F-Box Protein Ligases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Ubiquitin
  • Ubiquitin-Protein Ligases