PHOSPHORYLATION OF SER(262) STRONGLY REDUCES BINDING OF TAU-PROTEIN TO MICROTUBULES - DISTINCTION BETWEEN PHF-LIKE IMMUNOREACTIVITY AND MICROTUBULE-BINDING

Tau protein, a component of Alzheimer paired helical filaments, can be phosphorylated by several kinases. Of particular interest is the phos phorylation at Ser/Thr-Pro motifs because the resulting state of tau i s similar to that found in Alzheimer's disease, as judged by its immun oreactivity. This state can be mimicked by a brain extract kinase acti vity and by MAP kinase. We have now studied the effect of these modes of phosphorylation on the interaction between tau and microtubules. Al though MAP kinase efficiently phosphorylates many Ser/Thr-Pro motifs o f tau, its effect on microtubule binding is only moderate. By contrast , phosphorylation of a single residue, Ser262, has a major effect on b inding. Ser262 is not phosphorylated by MAP kinase or other proline-di rected kinases, but is phosphorylated by a 35/41 kd kinase in brain, w hose purification is described.