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Structural basis for recruitment of human flap endonuclease 1 to PCNA.

Flap endonuclease-1 (FEN1) is a key enzyme for maintaining genomic stability and replication. Proliferating cell nuclear antigen (PCNA) binds FEN1 and stimulates its endonuclease activity. The structural basis of the FEN1-PCNA interaction was revealed by the crystal structure of the complex between human FEN1 and PCNA. The main interface involves the C-terminal tail of FEN1, which forms two beta-strands connected by a short helix, the betaA-alphaA-betaB motif, participating in beta-beta and hydrophobic interactions with PCNA. These interactions are similar to those previously observed for the p21CIP1/WAF1 peptide. However, this structure involving the full-length enzyme has revealed additional interfaces that are involved in the core domain. The interactions at the interfaces maintain the enzyme in an inactive 'locked-down' orientation and might be utilized in rapid DNA-tracking by preserving the central hole of PCNA for sliding along the DNA. A hinge region present between the core domain and the C-terminal tail of FEN1 would play a role in switching the FEN1 orientation from an inactive to an active orientation.

Pubmed ID: 15616578

Authors

  • Sakurai S
  • Kitano K
  • Yamaguchi H
  • Hamada K
  • Okada K
  • Fukuda K
  • Uchida M
  • Ohtsuka E
  • Morioka H
  • Hakoshima T

Journal

The EMBO journal

Publication Data

February 23, 2005

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Flap Endonucleases
  • Humans
  • Methanococcus
  • Models, Molecular
  • Molecular Sequence Data
  • Proliferating Cell Nuclear Antigen
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyrococcus furiosus
  • Sequence Alignment