• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.

The ubiquitin-mediated proteolysis of cyclin E plays a central role in cell-cycle progression, and cyclin E accumulation is a common event in cancer. Cyclin E degradation is triggered by multisite phosphorylation, which induces binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7 complex bound to cyclin E peptides identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one. Biochemical data indicate that the closely related yeast SCF(Cdc4) complex recognizes the multisite phosphorylated Sic1 substrate similarly and identify three doubly phosphorylated Sic1 degrons, each capable of high-affinity interactions with two Cdc4 phosphate binding sites. A model that explains the role of multiple cyclin E/Sic1 degrons is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4 dimerization increases the rate and processivity of Sic1 ubiquitination in vitro.

Pubmed ID: 17434132

Authors

  • Hao B
  • Oehlmann S
  • Sowa ME
  • Harper JW
  • Pavletich NP

Journal

Molecular cell

Publication Data

April 13, 2007

Associated Grants

  • Agency: NIA NIH HHS, Id: R01 AG011085

Mesh Terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Dimerization
  • F-Box Proteins
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Phosphopeptides
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • S-Phase Kinase-Associated Proteins
  • SKP Cullin F-Box Protein Ligases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Serine
  • Structure-Activity Relationship
  • Substrate Specificity
  • Threonine
  • Transfection
  • Ubiquitin
  • Ubiquitin-Protein Ligases