作为一种主要的微管相关蛋白,tau参与中枢神经系统微管的组装。然而,在病理条件下,tau组装成淀粉样蛋白丝。通过液-液相分离(LLPS)形成的液滴是最近确定的tau的组装状态,并且可能对tau的生理功能和tau聚集体的形成具有主要影响。14-3-3蛋白在各种组织中普遍表达并调节多种生物过程。在这项工作中,我们证明了14-3-3ζ被募集到tau液滴中并通过体外测定调节tauLLPS。虽然在14-3-3ζ的存在下,液滴内tau分子的迁移率不受影响,液滴的数量和大小可以显著变化。机理研究表明,14-3-3ζ通过与富含脯氨酸的结构域和tau的微管结合结构域的静电相互作用和疏水相互作用来调节tauLLPS。令人惊讶的是,14-3-3ζ的无序C末端尾而不是两亲性结合沟起关键作用。我们的发现不仅提供了一个新的维度来理解14-3-3蛋白和tau之间的相互作用,但也表明14-3-3蛋白可能在调节其结合伴侣的LLPS中发挥重要作用。
As a major microtubule-associated protein, tau is involved in the assembly of microtubules in the central nervous system. However, under pathological conditions tau assembles into amyloid filaments. Liquid droplets formed by liquid-liquid phase separation (LLPS) are a recently identified assembly state of tau and may have a major effect on the physiological function of tau and the formation of tau aggregates. 14-3-3 proteins are ubiquitously expressed in various tissues and regulate a wide variety of biological processes. In this work, we demonstrate that 14-3-3ζ is recruited into tau droplets and regulates tau LLPS by in vitro assays. While the mobility of tau molecules inside the droplets is not affected in the presence of 14-3-3ζ, the amount and size of droplets can vary significantly. Mechanistic studies reveal that 14-3-3ζ regulates tau LLPS by electrostatic interactions and hydrophobic interactions with the proline-rich domain and the microtubule-binding domain of tau. Surprisingly, the disordered C-terminal tail rather than the amphipathic binding groove of 14-3-3ζ plays a key role. Our findings not only provide a novel dimension to understand the interactions between 14-3-3 proteins and tau, but also suggest that 14-3-3 proteins may play an important role in regulating the LLPS of their binding partners.