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

Abstract

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.

Androgen receptor CAG and GGC polymorphisms in Mediterraneans: repeat dynamics and population relationships

“…A more recent study (Buchanan et al 2004) reveals that under a critical size of 16 CAG repeats, the conformational structure resulting from the short polyglutamine tract encoded by these repeats could enhance the binding of specific transcriptional coactivators, resulting in higher AR activity even at lower androgen concentrations. The Ivory Coast and all North African samples show high frequencies of CAG alleles £ 18 repeats.…”

The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case-control study and meta-analysis

“…Normal CAG repeat number varies from 11 to 36 [9]. Previous studies in vitro have demonstrated that CAG repeat number shows an inverse correlation with AR activity [9][10][11][12][13][14]. Hence, it's not difficult to understand that shorter CAG repeats, increasing AR activity, are associated with prostate cancer [15,16], hirsutism [17] and hyperandrogenism in ovary [18,19], while longer CAG repeats, decreasing AR activity, are related to hypoandrogenicity [20] and male infertility due to impaired sperm production [10,21].…”

Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence

“…Whereas extreme CAG lengths (>40 repeats) cause spinal muscular atrophy (i.e., Kennedy disease), a higher number of repeats within the normal range (>90% alleles have between 16 and 29 CAG repeats) have been associated with lower androgen receptor transactivational capacity in numerous in vitro studies (27)(28)(29)(30)(31), and with androgenic phenotypes in transgenic mice (32). In humans, shorter CAG lengths have been associated with accentuation of several sexually differentiated somatic phenotypes in males (33) and with the presence of hyperandrogenic syndromes in females (34) (although negative studies also exist e.g., ref.…”