Structure-function analysis of the androgen receptor in Kennedy's disease patients
The androgen receptor (AR) is a ligand-dependent transcription factor which is part o the nuclear receptor superfamily. Binding of androgens testosterone or 5 a-reduced dihydrotestosterone activates the receptor causing it to localise to the nucleus where it binds to specific DNA androgen response elements in androgen-regulated genes and activates transcription. The N-terminal domain (NTD) of the AR contains several polyamino acid repeat sequences. The polyglycine repeat and one of the polyglutamine (poly-Q) repeats are polymorphic and changes in length are associated with disease. Expansion of the poly-Q tract in the AR NTD causes spatial bulbar muscular atrophy (SBMA) or Kennedy’s disease. SBMA is one of a group of nine neurodegenerative diseases caused by a poly-Q repeat tract expansion. The function of the majority of poly-Q disease proteins is unknown hence the AR provides an opportunity to investigate poly-Q polymorphic effects on protein structure and function. Structural analysis indicates an expansion of the poly-Q tract increases a-helical secondary structure content in the AR NTD. An increase in poly-Q tract length also enhances binding to the C-terminal domain of p160 co-activator proteins SRC-1a and TIF2 as well as to the TFIID component TAFII130 drosophila homolog dTAFII110. Phosphorylation of the AR NTD by kinases CKII, GSK-3, MAPK and PKA is enhanced by deletion of the poly-Q tract. MAP kinase phosphorylation of the AR NTD is also increased by the expansion of the poly-Q tract. An increase in protein structure caused by expansion of the poly-Q tract in the AR NTD correlates to enhanced protein binding and changes in MAPK phosphorylation which, may influence receptor activity and play a role in the pathogenesis of SBMA.