Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
The Laboratory of the Physics of Living Matter, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Angew Chem Int Ed Engl. 2017 May 2;56(19):5202-5207. doi: 10.1002/anie.201611750. Epub 2017 Mar 23.
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 α-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.
在此，我们通过蛋白质半合成技术首次研究赖氨酸乙酰化和磷酸化的影响，以及这些修饰之间的相互作用对突变亨廷顿外显子 1（Httex1）的结构和聚集的影响。我们的研究结果表明，T3 位的磷酸化可稳定 N 端 17 个氨基酸（Nt17）的α-螺旋构象，并显著抑制突变型 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 的乙酰化，但不是 K9 或 K15 的乙酰化，逆转了 T3 位磷酸化的抑制作用。总之，我们的研究结果为 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，并表明其聚集以及可能的功能受涉及不同 PTM 之间相互作用的调节机制控制。
