Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, Maharashtra, India.
Sci Rep. 2019 Jul 25;9(1):10795. doi: 10.1038/s41598-019-47249-7.
Tau is a microtubule-associated protein whose C-terminal domain consisting of four repeat regions R1, R2, R3 and R4 binds to microtubules to stabilize them. In several neurodegenerative diseases, tau detaches from microtubules to form insoluble aggregates leading to tauopathy. Microtubules are made up of αβ tubulin subunits. Seven α-tubulin and nine β-tubulin isotypes have been reported to be present in humans till date. These tubulin isotypes show residue composition variations mainly at C-terminal region and bind to motor proteins and anti-mitotic drugs differently. These tubulin isotypes show tissue specific expression as their relative proportion varies significantly in different type of cells. It is also known that tau binds differently to different cell lines and can either promote or demote microtubule polymerization. However, the relative binding affinity of tau to the different β-tubulin isotypes present in different cell lines is completely unknown. Here, we study relative binding affinity of Tau repeat region R2 to neuronal specific tubulin isotypes βI, βIIb, and βIII using molecular modelling approach. The order of binding energy of tau with tubulin is βIII > βIIb > βI. Our strategy can be potentially adapted to understand differential binding affinity of tau towards β-tubulin isotypes present in other cell lines.
Tau 是一种微管相关蛋白，其由四个重复区域 R1、R2、R3 和 R4 组成的 C 端结构域与微管结合以稳定它们。在几种神经退行性疾病中，tau 从微管上脱离形成不溶性聚集体，导致 tau 病。微管由αβ微管蛋白亚基组成。迄今为止，已报道人类存在七种α-微管蛋白和九种β-微管蛋白同工型。这些微管蛋白同工型主要在 C 末端区域表现出残基组成的变化，并与马达蛋白和抗有丝分裂药物不同结合。这些微管蛋白同工型表现出组织特异性表达，因为它们在不同类型的细胞中的相对比例差异很大。已知 tau 与不同的细胞系结合不同，可以促进或抑制微管聚合。然而，tau 与不同细胞系中存在的不同β-微管蛋白同工型的相对结合亲和力完全未知。在这里，我们使用分子建模方法研究 Tau 重复区 R2 与神经元特异性微管蛋白同工型βI、βIIb 和βIII 的相对结合亲和力。tau 与微管结合的能量顺序为βIII>βIIb>βI。我们的策略可以潜在地适应于理解 tau 对其他细胞系中存在的β-微管蛋白同工型的差异结合亲和力。
