CNRS, Université Paris Cité, UPR 9080, Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, 13 rue Pierre et Marie Curie, 75005 Paris, France.
Institut Universitaire de France (IUF), 75005 Paris, France.
J Phys Chem B. 2022 Jul 7;126(26):4849-4856. doi: 10.1021/acs.jpcb.2c02836. Epub 2022 Jun 27.
A tau R3-R4 domain spanning residues 306-378 was shown to form an amyloid fibril core of a full-length tau in the brain of patients with Alzheimer's disease. Recently, we studied the dynamics of a tau R3-R4 monomer at the surface of a lipid bilayer model and revealed deep insertion of the amino acids spanning the PHF6 motif (residues 306-311) and its flanking residues. Here, we explore the membrane-associated conformational ensemble of a tau R3-R4 dimer by means of atomistic molecular dynamics. Similar to the monomer simulation, the R3-R4 dimer has the propensity to form β-hairpin-like conformation. Unlike the monomer, the dimer shows insertion of the C-terminal R4 region and transient adsorption of the PHF6 motif. Taken together, these results reveal the multiplicity of adsorption and insertion modes of tau into membranes depending on its oligomer size.
一种跨越残基 306-378 的 tau R3-R4 结构域被证明可以在阿尔茨海默病患者大脑中的全长 tau 中形成淀粉样纤维核心。最近，我们研究了在脂质双层模型表面的 tau R3-R4 单体的动力学，并揭示了横跨 PHF6 基序（残基 306-311）及其侧翼残基的氨基酸的深度插入。在这里，我们通过原子分子动力学来探索 tau R3-R4 二聚体与膜相关的构象整体。与单体模拟类似，R3-R4 二聚体具有形成β发夹样构象的倾向。与单体不同，二聚体显示 C 末端 R4 区域的插入和 PHF6 基序的瞬时吸附。总之，这些结果揭示了 tau 进入膜的吸附和插入模式的多样性取决于其寡聚体的大小。
