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Journal of Virology, June 2008, p. 5672-5682, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.01330-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Vpr Binds to the N Lobe of the Wee1 Kinase Domain and Enhances Kinase Activity for Cdc2{triangledown}

Masakazu Kamata,1 Nobumoto Watanabe,3 Yoshiko Nagaoka,2 and Irvin S. Y. Chen1*

Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, David Geffen School of Medicine, 615 Charles E. Young Dr. South, BSRB 173, Los Angeles, California 90095,1 Department of Molecular and Medical Pharmacology, University of California at Los Angeles, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, California 90095,2 Antibiotics Laboratory, Discovery Research Institute, Riken 2-1, Hirosawa, Wako, Saitama 351-0198, Japan3

Received 18 June 2007/ Accepted 26 March 2008

Human immunodeficiency virus type 1 Vpr is a virion-associated accessory protein that has multiple activities within an infected cell. One of the most dramatic effects of Vpr is the induction of cell cycle arrest at the G2/M boundary, followed by apoptosis. This effect has implications for CD4+ cell loss in AIDS. In normal cell cycle regulation, Wee1, a key regulator for G2-M progression, phosphorylates Tyr15 on Cdc2 and thereby blocks the progression of cells into M phase. We demonstrate that Vpr physically interacts with Wee1 at the N lobe of the kinase domain analogous to that present in other kinases. This interaction with Vpr enhances Wee1 kinase activity for Cdc2. Overexpression of Wee1 kinase-deficient mutants competes for Vpr-mediated cell cycle arrest, and deletion of the region of Wee1 that binds Vpr abrogates that competition. However, the Vpr mutants I74P and I81P, which fail to induce G2 arrest, can bind to and increase the kinase activity of Wee1 to the same extent as wild-type Vpr. Therefore, we conclude that the binding of Vpr to Wee1 is not sufficient for Vpr to activate the G2 checkpoint, and it may reflect an independent function of Vpr.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, David Geffen School of Medicine, 615 Charles E. Young Dr. South, BSRB 173, Los Angeles, CA 90095. Phone: (310) 825-4793. Fax: (310) 267-1875. E-mail: syuchen{at}mednet.ucla.edu

{triangledown} Published ahead of print on 2 April 2008.

Journal of Virology, June 2008, p. 5672-5682, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.01330-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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