THE SWITCH OF TAU-PROTEIN TO AN ALZHEIMER-LIKE STATE INCLUDES THE PHOSPHORYLATION OF 2 SERINE PROLINE MOTIFS UPSTREAM OF THE MICROTUBULE BINDING REGION
THE SWITCH OF TAU-PROTEIN TO AN ALZHEIMER-LIKE STATE INCLUDES THE PHOSPHORYLATION OF 2 SERINE PROLINE MOTIFS UPSTREAM OF THE MICROTUBULE BINDING REGION
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DOI：
10.1002/j.1460-2075.1992.tb05204.x
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发表时间：
1992-04-01
期刊：
影响因子：
11.4
通讯作者：
MANDELKOW, E
中科院分区：
文献类型：
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作者：
BIERNAT, J;MANDELKOW, EM;MANDELKOW, E
阿尔茨海默病的成对螺旋丝(PHF)主要由微管相关蛋白tau组成。PHF tau与正常人脑tau的不同之处在于它具有更高的M(R)和特殊的磷酸化状态。然而，所涉及的蛋白激酶(S)、tau上的磷酸化位点以及由此引起的构象变化还知之甚少。在这里，我们展示了一种新的单抗AT8，它在体外记录了tau的PHF样状态，并描述了一种将正常tau转变为PHF样状态的激酶活性。AT8的表位约为200个残基，位于内部重复区域之外，需要丝氨酸199和/或202的磷酸化。这两种酶的后面都有一个脯氨酸，这表明该激酶的活性属于脯氨酸导向的激酶家族。AT8的表位与另一种磷酸化依赖的抗体TAU1的表位几乎一致[Binder，L.I.，Frankforter，A.和Rebhun，L.(1985)J.Cell Biol.，101,1371-1378]，但两者是互补的，因为TAU1需要去磷酸化的表位。
The paired helical filaments (PHFs) of Alzheimer's disease consist mainly of the microtubule-associated protein tau. PHF tau differs from normal human brain tau in that it has a higher M(r) and a special state of phosphorylation. However, the protein kinase(s) involved, the phosphorylation sites on tau and the resulting conformational changes are only poorly understood. Here we show that a new monoclonal antibody, AT8, records the PHF-like state of tau in vitro, and we describe a kinase activity that turns normal tau into a PHF-like state. The epitope of AT8 is around residue 200, outside the region of internal repeats and requires the phosphorylation of serines 199 and/or 202. Both of these are followed by a proline, suggesting that the kinase activity belongs to the family of proline-directed kinases. The epitope of AT8 is nearly coincident with that of another phosphorylation-dependent antibody, TAU1 [Binder,L.I., Frankfurter,A. and Rebhun,L. (1985) J. Cell Biol., 101, 1371-1378], but the two are complementary since TAU1 requires a dephosphorylated epitope.