School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram (IISER TVM), Maruthamala P.O, Thiruvananthapuram-695551, Kerala, India.
Chemistry. 2017 Dec 1;23(67):16976-16979. doi: 10.1002/chem.201704555. Epub 2017 Nov 15.
Direct binding of divalent metal ion, especially Zn , have been shown to increase the rate of tau aggregation and enhance tau toxicity in cells. Hence, understanding the molecular basis of the Zn -accelerated tau aggregation can potentially determine the molecular interactions modulating tau aggregation. Herein, we show that Zn coordinates through the cysteine in R3 repeat and significantly accelerates the aggregation rate of the three repeat tau constructs (K19) but that the coordination is incapable of increasing the aggregation rate of the 20 amino acid peptide derived from the R3 repeat (R3) of tau. The NMR characterization of the binding of Zn to K19, together with the aggregation studies with K19, R3 and R4 peptides, reveal the presence of an aggregation-inhibitory interaction between the R3 and R4 repeat of K19. Our data show that binding of Zn to R3 repeat of tau, weaken the aggregation-inhibiting influence between R3 and R4 repeats, leading to faster aggregation of tau protein.
二价金属离子（尤其是 Zn ）的直接结合已被证明会增加 tau 聚集的速度，并增强细胞中的 tau 毒性。因此，了解 Zn 加速 tau 聚集的分子基础可能有助于确定调节 tau 聚集的分子相互作用。在此，我们发现 Zn 通过 R3 重复中的半胱氨酸配位，并显著加速了三重复 tau 构建体（K19）的聚集速率，但配位不能增加源自 tau 的 R3 重复的 20 个氨基酸肽（R3）的聚集速率。Zn 与 K19 结合的 NMR 特性以及 K19、R3 和 R4 肽的聚集研究表明，K19 的 R3 和 R4 重复之间存在聚集抑制相互作用。我们的数据表明，Zn 与 tau 的 R3 重复结合，削弱了 R3 和 R4 重复之间的聚集抑制影响，导致 tau 蛋白更快聚集。
