Site‐specific effects of tau phosphorylation on its microtubule assembly activity and self‐aggregation

F Liu, B Li, EJ Tung, I Grundke‐Iqbal… - European Journal of …, 2007 - Wiley Online Library
F Liu, B Li, EJ Tung, I Grundke‐Iqbal, K Iqbal, CX Gong
European Journal of Neuroscience, 2007Wiley Online Library
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 …
Abstract
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‐3β 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 (∼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.
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