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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts.

Kennedy's disease is a degenerative disorder of motor neurons caused by the expansion of a glutamine tract near the amino terminus of the androgen receptor (AR). Ligand binding to the receptor is associated with several post-translational modifications, but it is poorly understood whether these affect the toxicity of the mutant protein. Our studies now demonstrate that mutation of lysine residues in wild-type AR that are normally acetylated in a ligand-dependent manner mimics the effects of the expanded glutamine tract on receptor trafficking, misfolding, and aggregation. Mutation of lysines 630 or 632 and 633 to alanine markedly delays ligand-dependent nuclear translocation. The K632A/K633A mutant also undergoes ligand-dependent misfolding and aggregation similar to the expanded glutamine tract AR. This acetylation site mutant exhibits ligand-dependent 1C2 immunoreactivity, forms aggregates that co-localize with Hsp40, Hsp70, and the ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP), and inhibits proteasome function. Ligand-dependent nuclear translocation of the wild-type receptor and misfolding and aggregation of the K632A/K633A mutant are blocked by radicicol, an Hsp90 inhibitor. These data identify a novel role for the acetylation site as a regulator of androgen receptor subcellular distribution and folding and indicate that ligand-dependent aggregation is dependent upon intact Hsp90 function.[1]

References

  1. Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts. Thomas, M., Dadgar, N., Aphale, A., Harrell, J.M., Kunkel, R., Pratt, W.B., Lieberman, A.P. J. Biol. Chem. (2004) [Pubmed]
 
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