Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation.
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172-251) and C-terminal tail (residues 368-441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self-aggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3beta increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMP-dependent protein kinase diminished its activity (approximately 70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.
Liu
Fei
F
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Li
Bin
B
Tung
E-Jan
EJ
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
Gong
Cheng-Xin
CX
D016475:3T3 Cells; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*; D000097603:Dyrk Kinases
D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D011392:Proline; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D016875:tau Proteins; D000097603:Dyrk Kinases; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat