Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6
Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6
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DOI：
10.1002/anie.201611750
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发表时间：
2017-05-02
影响因子：
16.6
通讯作者：
Lashuel, Hilal A.
中科院分区：
文献类型：
--
作者：
Chiki, Anass;DeGuire, Sean M.;Lashuel, Hilal A.
在此，我们利用蛋白质半合成技术首次研究了赖氨酸乙酰化和磷酸化的影响，以及这些修饰之间的串扰对突变亨廷顿外显子1（Httex1）的结构和聚集的影响。我们的结果表明，T3 处的磷酸化稳定了 N 端 17 个氨基酸 (Nt17) 的螺旋构象，并显着抑制突变体 Httex1 的聚集。单个赖氨酸残基 K6、K9 或 K15 的乙酰化对 Httex1 聚集没有影响。有趣的是，K6 处的乙酰化（而非 K9 或 K15 处）逆转了 T3 磷酸化的抑制作用。总之，我们的结果为 Nt17 翻译后修饰在调节 Httex1 的结构和聚集中的作用提供了新的见解，并表明其聚集及其可能的功能是由涉及不同 PTM 之间串扰的调节机制控制的。
Herein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the -helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs.