Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3.
Machado-Joseph disease (MJD) is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract in MJD-1 gene product, ataxin-3. Recently, studies show that phosphorylation of polyglutamine disease proteins, such as huntingtin, ataxin-1 and DRPLA, plays an important role in regulating pathogenesis. However, the kinase that phosphorylates ataxin-3 remains unknown. Here we show that S256 site in ataxin-3 is phosphorylated by GSK 3beta. Moreover, S256A mutant of expanded ataxin-3 forms high molecular weight protein aggregation, whereas S256D mutant and expanded ataxin-3 without mutation on this site are monomeric. The molecular chaperone Hsp70 represses the aggregation of S256A mutant. Our results imply that phosphorylation of serine 256 in ataxin-3 by GSK 3beta regulates ataxin-3 aggregation.
Pubmed ID: 17434145 RIS Download
Binding Sites | Cell Line | Enzyme Activation | Glycogen Synthase Kinase 3 | Humans | Kidney | Multiprotein Complexes | Nerve Tissue Proteins | Nuclear Proteins | Phosphorylation | Protein Binding | Repressor Proteins | Serine