Kizhakkeduth Safwa T, Abdul Vahid Arshad, Oliyantakath Hassan Muhammed Shafeek, Parambil Anagha K, Jain Parul, Vijayan Vinesh
School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram (IISER TVM), Vithura, Thiruvananthapuram 695551, India.
School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram (IISER TVM), Vithura, Thiruvananthapuram 695551, India.
ACS Chem Neurosci. 2024 Oct 7. doi: 10.1021/acschemneuro.4c00456.
The interaction of tau protein with other key proteins essential for stress granule formation determines their functional and pathological impact. In a biological framework, the synergy between Alzheimer's associated tau protein and the stress granule core protein TIA1 is widely recognized. However, the molecular details of this association remain unclear. In this study, we throw light on the importance of the state in which the TIA1 exists in mediating its association with the tau protein. Investigations were carried out on the three repeat constructs of tau (K19) and different structures formed by TIA1. Specifically, the condensate formed by TIA1 full-length (TIA1-FL) protein as well as fibril formed by low complexity domain of TIA1 (TIA1-LCD). The dynamics of K19 inside TIA1-FL condensates and the aggregation kinetics of K19 in the presence of TIA1-LCD fibrils were examined using various biophysical techniques. Relaxation-based solution NMR spectroscopic investigations suggest a weak interaction with TIA1 condensates and indicated a reduction in the dynamics of K19 within these TIA1 condensates. In contrast, a significant interaction was observed between K19, and TIA1-LCD fibrils primarily mediated through KCGS and VQIVYKPVDLSKV. Our findings emphasize that the interaction between Tau and TIA1 varies depending on whether TIA1 is in its physiological condensate form or its pathological fibril state.
tau蛋白与应激颗粒形成所必需的其他关键蛋白之间的相互作用决定了它们的功能和病理影响。在生物学框架中，阿尔茨海默病相关tau蛋白与应激颗粒核心蛋白TIA1之间的协同作用已得到广泛认可。然而，这种关联的分子细节仍不清楚。在本研究中，我们揭示了TIA1存在状态在介导其与tau蛋白关联中的重要性。对tau的三种重复构建体（K19）和TIA1形成的不同结构进行了研究。具体而言，研究了TIA1全长（TIA1-FL）蛋白形成的凝聚物以及TIA1低复杂性结构域（TIA1-LCD）形成的原纤维。使用各种生物物理技术研究了K19在TIA1-FL凝聚物中的动力学以及在TIA1-LCD原纤维存在下K19的聚集动力学。基于弛豫的溶液核磁共振光谱研究表明K19与TIA1凝聚物之间存在弱相互作用，并表明这些TIA1凝聚物中K19的动力学降低。相比之下，观察到K19与TIA1-LCD原纤维之间存在显著相互作用，主要通过KCGS和VQIVYKPVDLSKV介导。我们的研究结果强调，Tau与TIA1之间的相互作用取决于TIA1是处于其生理凝聚物形式还是病理原纤维状态。
