Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2.

Substrates of the E3 ubiquitin ligase CRL4(Cdt2), including Cdt1 and p21, contain a PCNA-binding motif called a PIP box. Upon binding of the PIP box to PCNA on chromatin, CRL4(Cdt2) is recruited and the substrate is ubiquitylated. Importantly, a PIP box cannot be sufficient for destruction, as most PIP box ...
proteins are stable. Using Xenopus egg extracts, we identify two sequence elements in CRL4(Cdt2) substrates that promote their proteolysis: a specialized PIP box that confers exceptionally efficient PCNA binding and a basic amino acid 4 residues downstream of the PIP box, which recruits CRL4(Cdt2) to the substrate-PCNA complex. We also identify two mechanisms that couple CRL4(Cdt2)-dependent proteolysis to the chromatin-bound form of PCNA, ensuring that this proteolysis pathway is active only in S phase or after DNA damage. Thus, CRL4(Cdt2) recognizes an unusual degron, which is assembled specifically on chromatin via the binding of a specialized PIP box to PCNA.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Cell Cycle Proteins, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, DNA-Binding Proteins, Flap Endonucleases, Humans, Immunoprecipitation, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mutation, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Ubiquitin-Protein Ligases, Xenopus, Xenopus Proteins
Mol. Cell
Date: Jul. 10, 2009
Download Curated Data For This Publication
138666
Switch View:
  • Interactions 4