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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action
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Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action

机译：微管相关蛋白tau的寡聚化是由其N端序列介导的：对正常和病理性tau作用的影响

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摘要

Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal 'projection domains' aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly. Native gel analyses of full-length tau and deletion constructs demonstrate that the N-terminal region leads to multiple bands, consistent with oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment (tau(45-230)) assembles into heptamers/octamers. Ferguson analyses of denaturing gels demonstrates that tau(45-230) can dimerize even in sodium dodecyl sulfate. Atomic force microscopy reveals multiple levels of oligomerization by both full-length tau and tau(45-230). Finally, ion mobility-mass spectrometric analyses of tau(106-144), a small peptide containing the core of the hypothesized dimerization region, also demonstrate oligomerization. Thus, multiple independent strategies demonstrate that the N-terminal region of tau can mediate higher order oligomerization, which may have important implications for both normal and pathological tau action.
机译：尽管进行了广泛的结构功能分析，但对正常和病理性tau作用的分子机制仍知之甚少。 C末端微管结合区如何调节微管动力学和束缚？ tau会以哪种生物物理形式从一个神经元向另一个神经元反突触转移，从而促进神经变性和痴呆？先前的生物化学/生物物理工作导致了这样一个假说，即tau可以通过以反平行方式排列的两个N端“投影域”之间的静电相互作用而二聚化，从而生成能够与多个微管蛋白亚基相互作用的多价复合物。我们试图直接测试此二聚化模型。全长tau和缺失构建体的天然凝胶分析表明，N末端区域导致多个条带，与寡聚化一致。 Ferguson对天然凝胶的分析表明，N末端片段（tau（45-230））组装成七聚体/八聚体。 Ferguson对变性凝胶的分析表明，tau（45-230）甚至在十二烷基硫酸钠中也可以二聚。原子力显微镜显示全长tau和tau都具有多个低聚水平（45-230）。最后，tau（106-144）的离子淌度质谱分析也证实了低聚，tau（106-144）是一种含有假定二聚区核心的小肽。因此，多种独立的策略表明tau的N端区域可以介导更高阶的寡聚，这可能对正常和病理性tau动作都具有重要意义。

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