C-H•••π interplay between Ile308 and Tyr310 residues in the third repeat of microtubule binding domain is indispensable for self-assembly of three- and four-repeat tau
C-H•••π interplay between Ile308 and Tyr310 residues in the third repeat of microtubule binding domain is indispensable for self-assembly of three- and four-repeat tau
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DOI：
10.1093/jb/mvs061
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发表时间：
2012-09-01
影响因子：
2.7
通讯作者：
Tomoo, Koji
中科院分区：
文献类型：
--
作者：
Sogawa, Koushirou;Okuda, Ryouhei;Tomoo, Koji
关于tau聚集的结构支架的信息在开发预防阿尔茨海默病（AD）的方法中是重要的。Tau含有微管结合结构域（MBD），其在其C-末端的一半中由31和32个相似残基的三个或四个重复组成。虽然tau聚集的关键事件被认为是由MBD第三重复序列中的短六肽（306）VQIVYK（311）形成β-折叠结构，但由于分子间和分子内二硫键的形成，其聚集途径在三重复和四重复MBD之间不同。因此，阐明三/四重复全长tau蛋白自组装所需的共同结构元件是一个重要的研究课题。在此基础上，我们进一步研究了MBD的聚集机制，发现MBD的第三个重复序列中Ile 308和Tyr 310侧链之间的C-H中心点π相互作用对于三/四重复的全长tau蛋白的自组装是必不可少的，这种相互作用为触发分子缔合提供了构象种子。基于一系列MBD和全长tau蛋白突变体的聚集行为，提出了一种可能的tau蛋白自缔合模型，并讨论了聚集形式（丝状或颗粒状）与缔合途径之间的关系。
Information on the structural scaffold for tau aggregation is important in developing a method of preventing Alzheimer's disease (AD). Tau contains a microtubule binding domain (MBD) consisting of three or four repeats of 31 and 32 similar residues in its C-terminal half. Although the key event in tau aggregation has been considered to be the formation of beta-sheet structures from a short hexapeptide (306)VQIVYK(311) in the third repeat of MBD, its aggregation pathway to filament formation differs between the three-and four-repeated MBDs, owing to the intermolecular and intramolecular disulphide bond formations, respectively. Therefore, the elucidation of a common structural element necessary for the self-assembly of three-/four-repeated full-length tau is an important research subject. Expanding the previous results on the aggregation mechanism of MBD, in this paper, we report that the C-H center dot center dot center dot pi interaction between the Ile308 and Tyr310 side chains in the third repeat of MBD is indispensable for the self-assembly of three-/four-repeated full-length tau, where the interaction provides a conformational seed for triggering the molecular association. On the basis of the aggregation behaviours of a series of MBD and full-length tau mutants, a possible self-association model of tau is proposed and the relationship between the aggregation form (filament or granule) and the association pathway is discussed.