Importance of Tyr310 residue in the third repeat of microtubule binding domain for filament formation of tau protein
Importance of Tyr310 residue in the third repeat of microtubule binding domain for filament formation of tau protein
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DOI：
10.1093/jb/mvp181
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发表时间：
2010-03-01
影响因子：
2.7
通讯作者：
Ishida, Toshimasa
中科院分区：
文献类型：
--
作者：
Nishiura, Chisato;Takeuchi, Kengo;Ishida, Toshimasa
抑制tau纤维化是阿尔茨海默病和其他神经退行性疾病的潜在治疗靶点。作为一系列抑制可溶性单体tau蛋白向成熟纤维转变的研究，本研究利用Tyr取代的微管结合结构域（MBD）突变体，通过荧光、圆二色光谱和电子显微镜研究了MBD第三重复序列（R3）中Tyr 310残基对MBD组装的影响。因此，清楚地显示了位于位置310而不是其他位置的Tyr残基的重要性。通过对R3重复肽的构象比较发现，Tyr残基对N端V（306）QIVYK（311）序列的刚性延伸结构有贡献，而Ala取代导致了延伸结构的变形，从而失去了聚集能力。本结果表明，与Tyr残基特异性相互作用的化合物或识别含有Tyr残基的区域的抗体成为抑制tau纤维化的候选物。
The inhibition of tau fibrillation is a potential therapeutic target for Alzheimer's and other neurodegenerative diseases. As a series of studies on inhibiting the transition of soluble monomeric tau into mature fibril, the effect of Tyr310 residue in the third repeat (R3) of the microtubule-binding domain (MBD) on the assembly of MBD was investigated using Tyr-substituted MBD mutants by fluorescence, circular dichroism spectroscopy and electron microscopy. Consequently, the importance of the Tyr residue located at position 310, not at other positions, was clearly shown. The conformational comparison of the Tyr310Ala-substituted R3 repeat peptide with the unsubstituted one showed that the Tyr residue contributes to the rigid extended structure of the N-terminal V(306)QIVYK(311) sequence, and its replacement by Ala leads to the deformation of the extended structure, consequently losing its aggregation ability. The present results indicate that a compound that interacts specifically with the Tyr residue or an antibody recognizing the region containing the Tyr residue becomes a candidate for inhibiting tau fibrillation.