Sengupta Amitabha, Novak Michal, Grundke-Iqbal Inge, Iqbal Khalid
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA.
FEBS Lett. 2006 Oct 30;580(25):5925-33. doi: 10.1016/j.febslet.2006.09.060. Epub 2006 Oct 5.
Microtubule associated protein tau, which is expressed in six alternatively spliced molecular isoforms in human brain, is abnormally hyperphosphorylated in Alzheimer disease and related tauopathies. Here, we show (i) that GSK-3alpha and neither GSK-3beta nor cdk5 can phosphorylate tau at Ser262 and phosphorylation at Ser235 by cdk5 primes phosphorylation at Thr231 by GSK-3alpha/beta; (ii) that tau isoforms with two N-terminal inserts (tau4L, tau3L) are phosphorylated by cdk5 plus GSK-3 at Thr231 markedly more than isoforms lacking these inserts (tau4, tau3); and (iii) that Thr231 is phosphorylated approximately 50% more in free tau than in microtubule-bound tau, and the phosphorylation at this site results in the dissociation of tau from microtubules. These findings suggest that the phosphorylation of tau at Thr231 and Ser262 by cdk5 plus GSK-3, which inhibits its normal biological activity, is regulated both by its amino terminal inserts and its physical state.
微管相关蛋白tau在人类大脑中以六种可变剪接的分子异构体形式表达，在阿尔茨海默病及相关tau蛋白病中会异常过度磷酸化。在此，我们发现：（i）糖原合酶激酶-3α（GSK-3α）能够使tau蛋白在Ser262位点发生磷酸化，而糖原合酶激酶-3β（GSK-3β）和周期蛋白依赖性激酶5（cdk5）则不能，并且cdk5使tau蛋白在Ser235位点发生磷酸化会引发GSK-3α/β使tau蛋白在Thr231位点发生磷酸化；（ii）具有两个N端插入片段的tau异构体（tau4L、tau3L）在Thr231位点被cdk5加GSK-3磷酸化的程度明显高于缺乏这些插入片段的异构体（tau4、tau3）；（iii）游离tau蛋白中Thr231位点的磷酸化程度比与微管结合的tau蛋白高约50%，并且该位点的磷酸化会导致tau蛋白与微管解离。这些发现表明，cdk5加GSK-3使tau蛋白在Thr231和Ser262位点发生磷酸化，从而抑制其正常生物学活性，这一过程受到其N端插入片段及其物理状态的双重调节。
