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

被引:156
作者
Buchanan, G
Yang, M
Cheong, A
Harris, JM
Irvine, RA
Lambert, PF
Moore, NL
Raynor, M
Neufing, PJ
Coetzee, GA
Tilley, WD
机构
[1] Univ Adelaide, Hanson Inst, Dame Roma Mitchell Canc Res Labs, Adelaide, SA, Australia
[2] Queensland Univ Technol, Ctr Mol Biotechnol, Sch Life Sci, Brisbane, Qld, Australia
[3] Univ So Calif, Dept Mol Microbiol & Immunol, USC Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA USA
[4] Univ So Calif, Dept Urol, USC Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA USA
[5] Univ So Calif, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA USA
关键词
D O I
10.1093/hmg/ddh181
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1677 / 1692
页数:16
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