Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau-tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275-280) and PHF6 (residues 306-311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease-specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.

中文翻译：

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tau 配对螺旋丝成核基序内的翻译后修饰扰乱微管相互作用和寡聚体形成。

翻译后修饰的 tau 是 tau 神经原纤维缠结的主要成分，是阿尔茨海默病和其他 tau 病变的病理标志。tau 微管 (MT) 结合域 (MBD) 内的翻译后修饰 (PTM) 包含两个作为 tau 聚集的关键成核区域的六肽基序，可以潜在地调节 tau 聚集以及与 MT 和膜的相互作用。在这里，我们描述了最近发现的 tau PTM（赖氨酸琥珀酰化）对 tau-微管蛋白相互作用的影响，并将这些与先前报道的两种 MBD 修饰（赖氨酸乙酰化和酪氨酸磷酸化）的影响进行了比较。由于在蛋白质中生成位点特异性 PTM 具有挑战性，我们使用短合成肽来量化位于 PHF6*（配对螺旋丝 [PHF] 残基 275-280）和 PHF6（残基 306-311）六肽基序内的三个位点特异性 PTM 对微管蛋白结合的影响：K280 乙酰化，Y310磷酸化和 K311 琥珀酰化。我们将这些效应与 MBD PTM 模拟点突变 K280Q、Y310E 和 K311E 观察到的效应进行了比较。最后，我们评估了这些 PTM 模拟突变对 MBD 膜结合和膜诱导的原纤维和寡聚体形成的影响。我们发现所有三个 PTM 都会干扰 tau MT 结合，其中 Y310 磷酸化发挥最强的作用。PTM 模拟突变部分概括了 PTM 对 MT 结合的影响，也破坏了 tau 膜结合和膜诱导的寡聚体和原纤维形成。这些结果意味着这些 PTM，