Glycogen synthase kinase-3beta is complexed with tau protein in brain microtubules.
In Alzheimer's disease, microtubule-associated protein tau is hyperphosphorylated by an unknown mechanism and is aggregated into paired helical filaments. Hyperphosphorylation causes loss of tau function, microtubule instability, and neurodegeneration. Glycogen synthase kinase-3beta (GSK3beta) has been implicated in the phosphorylation of tau in normal and Alzheimer's disease brain. The molecular mechanism of GSK3beta-tau interaction has not been clarified. In this study, we find that when microtubules are disassembled, microtubule-associated GSK3beta dissociates from microtubules. From a gel filtration column, the dissociated GSK3beta elutes as an approximately 400-kDa complex. When fractions containing the approximately 400-kDa complex are chromatographed through an anti-GSK3beta immunoaffinity column, tau co-elutes with GSK3beta. From fractions containing the approximately 400-kDa complex, both tau and GSK3beta co-immunoprecipitate with each other. GSK3beta binds to nonphosphorylated tau, and the GSK3beta-binding region is located within the N-terminal projection domain of tau. In vitro, GSK3beta associates with microtubules only in the presence of tau. From brain extract, approximately 6-fold more GSK3beta co-immunoprecipitates with tau than GSK3alpha. These data indicate that, in brain, GSK3beta is bound to tau within a approximately 400-kDa microtubule-associated complex, and GSK3beta associates with microtubules via tau.
Sun
Wei
W
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital and the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3T 1E2, Canada.
Qureshi
Hamid Y
HY
Cafferty
Patrick W
PW
Sobue
Kazuya
K
Agarwal-Mawal
Alka
A
Neufield
Katherine D
KD
Paudel
Hemant K
HK
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D015151:Immunoblotting; D008870:Microtubules / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016875:tau Proteins / Q000378:metabolism*
D018076:DNA, Complementary; D010455:Peptides; D016875:tau Proteins; D005982:Glutathione Transferase; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3