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J. Biol. Chem., Vol. 282, Issue 4, 2717-2728, January 26, 2007

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Crystal Structure of the HRDC Domain of Human Werner Syndrome Protein, WRN^*

From the Structural Biology Laboratory, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan

Werner syndrome is a human premature aging disorder characterized by chromosomal instability. The disease is caused by the functional loss of WRN, a member of the RecQ-helicase family that plays an important role in DNA metabolic pathways. WRN contains four structurally folded domains comprising an exonuclease, a helicase, a winged-helix, and a helicase-and-ribonuclease D/C-terminal (HRDC) domain. In contrast to the accumulated knowledge pertaining to the biochemical functions of the three N-terminal domains, the function of C-terminal HRDC remains unknown. In this study, the crystal structure of the human WRN HRDC domain has been determined. The domain forms a bundle of -helices similar to those of Saccharomyces cerevisiae Sgs1 and Escherichia coli RecQ. Surprisingly, the extra ten residues at each of the N and C termini of the domain were found to participate in the domain architecture by forming an extended portion of the first helix 1, and a novel looping motif that traverses straight along the domain surface, respectively. The motifs combine to increase the domain surface of WRN HRDC, which is larger than that of Sgs1 and E. coli.In WRN HRDC, neither of the proposed DNA-binding surfaces in Sgs1 or E. coli is conserved, and the domain was shown to lack DNA-binding ability in vitro. Moreover, the domain was shown to be thermostable and resistant to protease digestion, implying independent domain evolution in WRN. Coupled with the unique long linker region in WRN, the WRN HRDC may be adapted to play a distinct function in WRN that involves protein-protein interactions.

Received for publication, October 30, 2006 , and in revised form, November 21, 2006.

The atomic coordinates and structure factors (code 2E1E and 2E1F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a grant-in-aid from the NAIST foundation, a grant-in-aid for Young Scientists from the Japan Society for the Promotion of Science (JSPS), and a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to K. K.), and a Protein 3000 project from MEXT (to T. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence may be addressed. Tel.: 81-743-72-5573; Fax: 81-743-72-5579; E-mail: kkitano{at}is.naist.jp. ² To whom correspondence may be addressed. Tel.: 81-743-72-5570; Fax: 81-743-72-5579; E-mail: hakosima{at}bs.naist.jp.

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