Structural basis of nuclear import of flap endonuclease 1 (FEN1)

de Barros, Andrea C., Takeda, Agnes A. S., Chang, Chiung-Wen, Kobe, Bostjan and Fontes, Marcos R. M. (2012) Structural basis of nuclear import of flap endonuclease 1 (FEN1). Acta Crystallographica Section D: Biological Crystallography, 68 7: 743-750. doi:10.1107/S0907444912010281

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Author de Barros, Andrea C.
Takeda, Agnes A. S.
Chang, Chiung-Wen
Kobe, Bostjan
Fontes, Marcos R. M.
Title Structural basis of nuclear import of flap endonuclease 1 (FEN1)
Journal name Acta Crystallographica Section D: Biological Crystallography   Check publisher's open access policy
ISSN 0907-4449
1399-0047
Publication date 2012-07-01
Sub-type Article (original research)
DOI 10.1107/S0907444912010281
Open Access Status File (Publisher version)
Volume 68
Issue 7
Start page 743
End page 750
Total pages 8
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Collection year 2013
Language eng
Formatted abstract
Flap endonuclease 1 (FEN1) is a member of the nuclease family and is structurally conserved from bacteriophages to humans. This protein is involved in multiple DNA-processing pathways, including Okazaki fragment maturation, stalled replication-fork rescue, telomere maintenance, long-patch base-excision repair and apoptotic DNA fragmentation. FEN1 has three functional motifs that are responsible for its nuclease, PCNA-interaction and nuclear localization activities, respectively. It has been shown that the C-terminal nuclear localization sequence (NLS) facilitates nuclear localization of the enzyme during the S phase of the cell cycle and in response to DNA damage. To determine the structural basis of the recognition of FEN1 by the nuclear import receptor importin α, the crystal structure of the complex of importin α with a peptide corresponding to the FEN1 NLS was solved. Structural studies confirmed the binding of the FEN1 NLS as a classical bipartite NLS; however, in contrast to the previously proposed 354KRKX8KKK367 sequence, it is the 354KRX10KKAK369 sequence that binds to importin α. This result explains the incomplete inhibition of localization that was observed on mutating residues 365KKK367. Acidic and polar residues in the X10 linker region close to the basic clusters play an important role in binding to importin α. These results suggest that the basic residues in the N-terminal basic cluster of bipartite NLSs may play roles that are more critical than those of the many basic residues in the C-terminal basic cluster.
Keyword Importin α
Nuclear import pathway
Nuclear localization sequence
DNA-repair proteins
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Mon, 23 Jul 2012, 22:49:38 EST by Lucy O'Brien on behalf of School of Chemistry & Molecular Biosciences