Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylationdependent mechanism
Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylationdependent mechanism
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DOI：
10.1091/mbc.e16-01-0029
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发表时间：
2016-10-01
影响因子：
3.3
通讯作者：
Arnal, Isabelle
中科院分区：
文献类型：
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作者：
Ramirez-Rios, Sacnicte;Denarier, Eric;Arnal, Isabelle
微管动力学的适当调节对于细胞功能是必不可少的，并且涉及各种微管相关蛋白（MAP）。其中，末端结合蛋白（EB）聚集在微管加端，而结构MAPs结合沿着微管晶格。最近的数据表明，结构MAP tau调节EB在神经元中的亚细胞定位。然而，EB/tau相互作用的分子决定因素仍然未知，这种相互作用对微管动力学的影响也是未知的。在这里，我们研究EB/tau蛋白在无细胞系统和细胞模型中相互作用的机制。我们发现tau蛋白抑制微管末端的EB追踪。Tau和EB通过EB的C-末端区域和Tau的微管结合位点形成复合物。这两个结构域是tau对EB定位到微管末端的抑制活性所必需的。此外，tau微管结合位点内的磷酸化模拟突变S262 E损害EB/tau相互作用，并阻止tau对EB彗星的抑制作用。我们进一步表明，微管动力学参数的变化，这取决于EB和tau蛋白的组合活动。总的来说，我们的研究结果表明，tau直接拮抗EB功能通过磷酸化依赖性机制。这项研究强调了tau在EB调节中的新作用，这可能在神经退行性疾病中受损。
Proper regulation of microtubule dynamics is essential for cell functions and involves various microtubule-associated proteins (MAPs). Among them, end-binding proteins (EBs) accumulate at microtubule plus ends, whereas structural MAPs bind along the microtubule lattice. Recent data indicate that the structural MAP tau modulates EB subcellular localization in neurons. However, the molecular determinants of EB/tau interaction remain unknown, as is the effect of this interplay on microtubule dynamics. Here we investigate the mechanisms governing EB/tau interaction in cell-free systems and cellular models. We find that tau inhibits EB tracking at microtubule ends. Tau and EBs form a complex via the C-terminal region of EBs and the microtubule-binding sites of tau. These two domains are required for the inhibitory activity of tau on EB localization to microtubule ends. Moreover, the phosphomimetic mutation S262E within tau microtubule-binding sites impairs EB/tau interaction and prevents the inhibitory effect of tau on EB comets. We further show that microtubule dynamic parameters vary, depending on the combined activities of EBs and tau proteins. Overall our results demonstrate that tau directly antagonizes EB function through a phosphorylation-dependent mechanism. This study highlights a novel role for tau in EB regulation, which might be impaired in neurodegenerative disorders.