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J. Biol. Chem., Vol. 283, Issue 8, 5118-5126, February 22, 2008

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Structure of the DNA Repair Helicase Hel308 Reveals DNA Binding and Autoinhibitory Domains^*

From the Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland

Hel308 is a superfamily 2 helicase conserved in eukaryotes and archaea. It is thought to function in the early stages of recombination following replication fork arrest and has a specificity for removal of the lagging strand in model replication forks. A homologous helicase constitutes the N-terminal domain of human DNA polymerase Q. The Drosophila homologue mus301 is implicated in double strand break repair and meiotic recombination. We have solved the high resolution crystal structure of Hel308 from the crenarchaeon Sulfolobus solfataricus, revealing a five-domain structure with a central pore lined with essential DNA binding residues. The fifth domain is shown to act as an autoinhibitory domain or molecular brake, clamping the single-stranded DNA extruded through the central pore of the helicase structure to limit the helicase activity of the enzyme. This provides an elegant mechanism to tune the processivity of the enzyme to its functional role. Hel308 can displace streptavidin from a biotinylated DNA molecule, and this activity is only partially inhibited when the DNA is pre-bound with abundant DNA-binding proteins RPA or Alba1, whereas pre-binding with the recombinase RadA has no effect on activity. These data suggest that one function of the enzyme may be in the removal of bound proteins at stalled replication forks and recombination intermediates.

Received for publication, September 10, 2007 , and in revised form, November 2, 2007.

The atomic coordinates and structure factors (code 2va8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AM778123 [GenBank] .

^* This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC). The native structure of Hel308 was determined by the Scottish Structural Proteomics Facility, which is funded by the BBSRC, Scottish Funding Council, and The University of St. Andrews. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 44-1334-463792; E-mail: jhn{at}st-and.ac.uk.

³ To whom correspondence may be addressed. Tel.: 44-1334-463432; E-mail: mfw2{at}st-and.ac.uk.

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