Abstract
Although the linkage of polyglutamine (poly-Q) repeat expansion in the androgen receptor (AR) to Kennedy's disease (X-linked spinal and bulbar muscular atrophy) was a major step forward, the detailed molecular mechanism of how the change in poly-Q length contributes to the disease remains unclear. Here we report the identification of a nuclear G-protein, Ras-related nuclear protein/ARA24, as the first AR coactivator that can bind differentially with different lengths of poly-Q within AR. In the yeast and mammalian reciprocal interacting assays, our data suggested the interaction of AR N-terminal domain with ARA24 diminishes as the poly-Q length increases. The coactivation of ARA24 also diminishes with the poly-Q expansion within AR. Deletion of the acidic hexapeptide (DEDDDL) at the C terminus of ARA24 further enhances its AR coactivation. Together, our data suggest that poor interaction and weaker coactivation of ARA24 to the longer poly-Q AR in the X-linked spinal and bulbar muscular atrophied AR could contribute to the weaker transactivation of AR. The consequence of poor interaction and weak coactivation may eventually lead to the partial androgen insensitivity during the development of Kennedy's disease.
Highlights
Tial androgen receptor (AR)-associated proteins that may contribute to this disease
The present study demonstrates that ARA24 interacts with the AR poly-Q region and functions as an AR coactivator
The interaction between AR and ARA24 decreases with the expansion of AR poly-Q, as well as the coactivation of cotransfected ARA24 to the SBMA AR
Summary
Tial AR-associated proteins that may contribute to this disease. Using the yeast two-hybrid system we were able to find an AR coactivator, ARA24, that can differentially activate the AR with different poly-Q lengths within AR. Ran/ARA24 was purified as a complex with a chromatin-associated DNA-binding protein, RCC1 (regulator of chromosome condensation 1). RCC1 has been shown to function as a guanine nucleotide exchange factor on Ran/ARA24 by increasing its rate ϳ5 ϫ 105 times. During biochemical identification of Ran-associated protein, previous reports mainly revealed its functions in nuclear transport [8]. Over 50% of the affected males may have gynecomastia and reduced fertility, suggesting a defect in AR function [2]. This hypothesis was confirmed by finding an expansion of poly-Q in SBMA AR [3]. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF052578
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