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Human Molecular Genetics Advance Access originally published online on June 15, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 16 1677-1692
DOI: 10.1093/hmg/ddh181
Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved

Structural and functional consequences of glutamine tract variation in the androgen receptor

Grant Buchanan1, Miao Yang1, Albert Cheong1, Jonathan M. Harris2, Ryan A. Irvine3, Paul F. Lambert1, Nicole L. Moore1,{dagger}, Michael Raynor1,{ddagger}, Petra J. Neufing1,§, Gerhard A. Coetzee3 and Wayne D. Tilley1,*

1Dame Roma Mitchell Cancer Research Laboratories, Adelaide University/Hanson Institute, Adelaide, SA, Australia, 2Centre for Molecular Biotechnology, School of Life Sciences, Queensland University of Technology, Brisbane, QLD, Australia and 3Departments of Molecular Microbiology and Immunology, Urology and Preventative Medicine, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Received February 6, 2004; Revised April 26, 2004; Accepted June 1, 2004

The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat region, (CAG)n, in its N-terminal transactivation domain (NTD) that encodes a polyglutamine (polyQ) tract in the receptor protein. Whereas the length of the CAG repeat ranges from 6 to 39 in healthy individuals, the variations in repeat length both within and outside the normal range are associated with disease, including impaired spermatogenesis and Kennedy's disease, and with the risk of developing breast and prostate cancer. Whereas it has been proposed that the inverse relationship between polyQ tract length within the normal range and AR transactivation potential may be responsible for altered risk of disease, the molecular mechanisms underlying polyQ length modulation of AR function have not been elucidated. In this study, we provide detailed characterization of a somatic AR gene mutation detected in a human prostate tumor that results in interruption of the polyQ tract by two non-consecutive leucine residues (AR-polyQ2L). Compared with wtAR, AR-polyQ2L exhibits disrupted inter-domain communication (N/C interaction) and a lower protein level, but paradoxically has markedly increased transactivation activity. Molecular modeling and the response to cofactors indicate that the increased activity of AR-polyQ2L results from the presentation of a more stable platform for the recruitment of accessory proteins than wild-type AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (Q16–Q29) for maintenance of N/C interaction. That between 91 and 99% of AR alleles in different racial-ethnic groups encode a polyQ tract in the range of Q16–Q29 suggests that N/C interaction has been preserved as an essential component of androgen-induced AR signaling.

* To whom correspondence should be addressed at: Dame Roma Mitchell Cancer Research Laboratories, Adelaide University/Hanson Institute, PO Box 14 Rundle Mall, Adelaide, SA 5000, Australia. Tel: +61 882223225; Fax: +61 882223217; Email: wayne.tilley{at}imvs.sa.gov.au


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