Trinucleotide Repeats and Protein Folding and Disease: the Perspective From Studies With the Androgen Receptor

Abstract

The androgen receptor (AR), a ligand activated transcription factor plays a number of roles in reproduction, homeostasis and pathogenesis of disease. It has two major polymorphic sequences; a polyglutamine and a polyglycine repeat that determine the length of the protein and influence receptor folding, structure and function. Here, we review the role the folding of the AR plays in the pathogenesis of spinal-bulbar muscular atrophy (SBMA), a neuromuscular degenerative disease arising from expansion of the polyglutamine repeat. We discuss current management for SBMA patients and how research on AR structure function may lead to future drug treatments.

A cryptic transactivation domain of EZH2 binds AR and AR’s splice variant promoting oncogene activation and tumorous transformation

“…In particular, EZH2 forms the so-called EZH2-solo sites in a PRC2-independent fashion and binds AR, eliciting the noncanonical gene-activation effects in prostate cancer(18). In this report, we unveiled, for the first time, (i) that EZH2 utilizes a hidden EZH2 TAD to form interactions with AR and/or AR’s constitutively-active variant AR-V7; here, we further mapped the EZH2 TAD -interacting interfaces to at least two unstructured regions of AR— so-called polyQ- and polyG-containing sequences(43,44) with a property of intrinsically disorganized protein regions(45). These results suggest a multivalent protein-protein interaction involving un-structured protein sequences (TADs themselves often being unstructured) and possibly, liquid-liquid phase separation, which merits future studies.…”

Amino acid repeats avert mRNA folding through conservative substitutions and synonymous codons, regardless of codon bias

“…Although the molecular mechanism of such expansions are not clear, these changes underlie several genetic diseases of the “trinucleotide repeat disorder” family, such as the polyQ (poly-Gln) diseases, caused by expansion of the CAG (one of two Gln codons) repeats above a normal threshold number. Common examples include Huntington Disease (HD), Spinocerebellar ataxia-8, X-linked spinal tubular muscular atrophy (SBMA, or Kennedy disease), and certain forms of breast and prostate cancers, caused by polyQ-tract expansion in the AIB1 (“amplified in breast cancer gene 1”) and AR (androgen receptor) genes, respectively [ 10 , 11 , 12 , 13 ]. In the recent past, one AAR study investigated the physical properties and intracellular localization of 30-mer repeat polypeptides, recombinantly expressed in primate cells [14] .…”

Protein Misfolding Diseases

“…In fact, the devastating CNS glioblastomas exploits the unfolded protein response to allow their continued uncontrolled growth, becoming thus a potential target for treatment intervention, as reviewed by Michael Graner [9]. Spinal and bulbar muscular atrophy, is a neuromuscular degenerative disease that, as in the case of the better characterized Huntignton's disease, arises from expansion of the polyglutamine repeats, in this case in the androgen receptor, indicating that similar sequential changes might lead to different disorders depending on the protein target in which they occur, as reported by Folake A Orafidiya and Iain J McEwan [10]. In fact, the propensity of a protein to form amyloid assemblies is imprinted in its sequence and can be read using computational approaches.…”