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J. Biol. Chem., Vol. 279, Issue 29, 30643-30653, July 16, 2004

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An Androgen Receptor NH₂-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)^*

Bin He¶, Suxia Bai, Andrew T. Hnat, Rebecca I. Kalman, John T. Minges, Cam Patterson||, and Elizabeth M. Wilson**

From the Laboratories for Reproductive Biology and the Departments of Pediatrics, ^||Medicine, and ^**Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

The NH₂-terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH₂-terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH₂-terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH₂-terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH₂-terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH₂-terminal domains and other intrinsically unstructured transcriptional regulatory proteins.

Received for publication, March 19, 2004 , and in revised form, April 21, 2004.

^* This work was supported by United States Public Health Service Grant HD16910 from NICHD, National Institutes of Health; by Grant PO1-CA77739 from NCI, National Institutes of Health; by Cooperative Agreement U54-HD35041 as part of the Specialized Cooperative Centers Program in Reproductive Research of the National Institutes of Health; and by Fogarty International Center Grant R03TW001234 from the National Institutes of Health (to Frank S. French). 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.

^¶ Present address: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.

To whom correspondence should be addressed: Labs. for Reproductive Biology, CB 7500, Medical Biomolecular Research Bldg., Rm. 3340, 103 Mason Farm Rd., University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-966-5168; Fax: 919-966-2203; E-mail: emw{at}med.unc.edu.

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