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.
Sakurai
Shigeru
S
Structural Biology Laboratory, Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan.
Kitano
Ken
K
Yamaguchi
Hiroto
H
Hamada
Keisuke
K
Okada
Kengo
K
Fukuda
Kotaro
K
Uchida
Makiyo
M
Ohtsuka
Eiko
E
Morioka
Hiroshi
H
Hakoshima
Toshio
T
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D045585:Flap Endonucleases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D017017:Methanococcus / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020027:Pyrococcus furiosus / Q000201:enzymology; D016415:Sequence Alignment
D018809:Proliferating Cell Nuclear Antigen; D045585:Flap Endonucleases; C468317:FEN1 protein, human