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.
Fei
Erkang
E
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
Jia
Nali
N
Zhang
Tao
T
Ma
Xiaochuan
X
Wang
Hongfeng
H
Liu
Chao
C
Zhang
Wei
W
Ding
Lili
L
Nukina
Nobuyuki
N
Wang
Guanghui
G
D000067699:Ataxin-3; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*
D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C092341:ATXN3 protein, human; D000067699:Ataxin-3