An allosteric activator of the protein Hsp70 that promotes the clearance of neurotoxic molecules of polyglutamine-containing Androgen Receptor in a Drosophila model for spinobulbar muscular atrophy (SBMA) is reported this week in Nature Chemical Biology.
SBMA is a progressive neuromuscular disorder that is associated with a loss of motor neurons; it is caused by an expansion of a CAG nucleotide repeat in the gene encoding Androgen Receptor. This expansion increases the length of a polyglutamine tract that in turn disrupts protein folding and results in the toxic accumulation of the protein.
Andrew Lieberman, Jason Gestwicki and colleagues now show that a small-molecule activator of Hsp70-a chaperone that determines whether proteins will be degraded or not-can promote the degradation of toxic forms of Androgen Receptor (containing the expanded polyglutamine tract) in fly models for SBMA. They report that the small molecule acts by mimicking the activity of the co-chaperone Hip, by stabilizing a conformation of Hsp70 that is bound to the cofactor ADP, thereby increasing interaction between the chaperone and the toxic protein.