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J. Biol. Chem., Vol. 281, Issue 22, 15227-15237, June 2, 2006

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UvrB Domain 4, an Autoinhibitory Gate for Regulation of DNA Binding and ATPase Activity^*

Hong Wang¹, Matthew J. DellaVecchia¹, Milan Skorvaga, Deborah L. Croteau, Dorothy A. Erie^¶, and Bennett Van Houten²

From the Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, the Department of Molecular Genetics, Cancer Research Institute, Slovak Academy of Sciences, 83391 Bratislava, Slovakia, and the ^¶Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599

UvrB, a central DNA damage recognition protein in bacterial nucleotide excision repair, has weak affinity for DNA, and its ATPase activity is activated by UvrA and damaged DNA. Regulation of DNA binding and ATP hydrolysis by UvrB is poorly understood. Using atomic force microscopy and biochemical assays, we found that truncation of domain 4 of Bacillus caldotenax UvrB (UvrB4) leads to multiple changes in protein function. Protein dimerization decreases with an 8-fold increase of the equilibrium dissociation constant and an increase in DNA binding. Loss of domain 4 causes the DNA binding mode of UvrB to change from dimer to monomer, and affinity increases with the apparent dissociation constants on nondamaged and damaged single-stranded DNA decreasing 22- and 14-fold, respectively. ATPase activity by UvrB4 increases 14- and 9-fold with and without single-stranded DNA, respectively, and UvrB4 supports UvrA-independent damage-specific incision by Cho on a bubble DNA substrate. We propose that other than its previously discovered role in regulating protein-protein interactions, domain 4 is an autoinhibitory domain regulating the DNA binding and ATPase activities of UvrB.

Received for publication, February 15, 2006 , and in revised form, March 28, 2006.

^* This work was supported by the Intramural Research Program of the NIEHS, National Institutes of Health. 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 paper.

² To whom correspondence should be addressed: NIEHS, 111 Alexander Dr., P. O. Box 12233, Research Triangle Park, NC 27709. Tel.: 919-541-7752; Fax: 919-541-7593; E-mail: vanhout1{at}niehs.nih.gov.

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