Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Department of Physics, University of Illinois at Chicago, Chicago, Illinois, USA.
Protein Sci. 2023 Mar;32(3):e4581. doi: 10.1002/pro.4581.
Tau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-electron microscopy. Here, we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules.
Tau 作为典型的无规卷曲蛋白 (IDP)，可以结合多个靶点，包括微管和酸性膜。后两种表面都带有很高的负电荷，这增加了 tau 结合它们的模拟可能性。tau-微管复合物最近通过低温电子显微镜确定。在这里，我们使用分子动力学模拟来描述 tau K19 与酸性膜的动态结合。这种 IDP 可以分为三个重复，每个重复包含一个两亲性螺旋。这三个两亲性螺旋以及侧翼残基将蛋白质固定在膜界面上。模拟中两亲性螺旋之间的分离和膜定位通过已发表的 EPR 数据得到验证。tau 中单个残基与膜的接触概率与与微管的天然接触既有相似之处，也有区别。特别是，在重复中保守的一个赖氨酸与膜和微管形成相似的相互作用，保守的缬氨酸也是如此。这种部分模拟促进了 tau 对微管的膜锚定以及 tau 从膜到微管的转移。
