title: Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts.
abstract: 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.
authors.affiliation: Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
authors.forename: Monzy
authors.initials: M
authors.lastname: Thomas
authors.forename: Nahid
authors.initials: N
authors.lastname: Dadgar
authors.forename: Abhishek
authors.initials: A
authors.lastname: Aphale
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Harrell
authors.forename: Robin
authors.initials: R
authors.lastname: Kunkel
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000107:Acetylation; D001665:Binding Sites / Q000235:genetics; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D005973:Glutamine; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D008239:Lysine / Q000235:genetics; D018942:Macrolides; D009154:Mutation; D017354:Point Mutation; D017510:Protein Folding; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D008164:Luminescent Proteins; D018942:Macrolides; D011944:Receptors, Androgen; D005973:Glutamine; D049452:Green Fluorescent Proteins; C035359:monorden; D008239:Lysine