Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.
Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.
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DOI：
10.1042/bj20140372
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发表时间：
2014-08-15
期刊：
影响因子：
--
通讯作者：
Kuret J
中科院分区：
文献类型：
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作者：
Funk KE;Thomas SN;Schafer KN;Cooper GL;Liao Z;Clark DJ;Yang AJ;Kuret J
在阿尔茨海默病中，微管相关蛋白tau从神经元细胞骨架解离并聚集形成细胞质内含物。尽管tau Ser和Thr残基的过度磷酸化是tau功能障碍和聚集的既定触发因素，但tau修饰也延伸至Lys残基，从而提高了不同修饰特征根据位点占用抑制或促进聚集倾向的可能性。为了鉴定与正常tau功能相关的Lys残基修饰，通过质谱法表征从四个认知正常人脑分离的可溶性tau蛋白。发现主要的可检测的赖氨酸修饰是甲基化，其以分布在至少11个位点中的单甲基和二甲基赖氨酸残基的形式出现。与tau蛋白磷酸化位点不同，Lys甲基化的频率在介导微管结合和同型相互作用的微管结合重复区中最高。当纯化的重组人tau蛋白在体外通过还原甲基化进行修饰时，其促进微管蛋白聚合的能力被保留，而其聚集倾向在成核和延伸步骤中都大大减弱。这些数据确立了Lys甲基化是人脑中正常tau翻译后修饰特征的一部分，并表明它可以部分地起保护作用以防止病理性tau聚集。
In Alzheimer disease, the microtubule-associated protein tau dissociates from the neuronal cytoskeleton and aggregates to form cytoplasmic inclusions. Although hyper-phosphorylation of tau Ser and Thr residues is an established trigger of tau misfunction and aggregation, tau modifications extend to Lys residues as well, raising the possibility that different modification signatures depress or promote aggregation propensity depending on site occupancy. To identify Lys-residue modifications associated with normal tau function, soluble tau proteins isolated from four cognitively normal human brains were characterized by mass spectrometry methods. The major detectable Lys modification was found to be methylation, which appeared in the form of mono- and di-methyl Lys residues distributed among at least eleven sites. Unlike tau phosphorylation sites, the frequency of Lys methylation was highest in the microtubule binding repeat region that mediates both microtubule binding and homotypic interactions. When purified recombinant human tau was modified in vitro through reductive methylation, its ability to promote tubulin polymerization was retained, whereas its aggregation propensity was greatly attenuated at both nucleation and extension steps. These data establish Lys methylation as part of the normal tau post-translational modification signature in human brain, and suggest that it can function in part to protect against pathological tau aggregation.