Molecular Interactions\nbetween Tau Protein and TIA1:\nDistinguishing Physiological Condensates from Pathological Fibrils

The\ninteraction of tau protein with other key proteins essential\nfor stress granule formation determines their functional and pathological\nimpact. In a biological framework, the synergy between Alzheimer’s\nassociated tau protein and the stress granule core protein TIA1 is\nwidely recognized. However, the molecular details of this association\nremain unclear. In this study, we throw light on the importance of\nthe state in which the TIA1 exists in mediating its association with\nthe tau protein. Investigations were carried out on the three repeat\nconstructs of tau (K19) and different structures formed by TIA1.\nSpecifically, the condensate formed by TIA1 full-length (TIA1-FL)\nprotein as well as fibril formed by low complexity domain of TIA1\n(TIA1-LCD). The dynamics of K19 inside TIA1-FL condensates and the\naggregation kinetics of K19 in the presence of TIA1-LCD fibrils were\nexamined using various biophysical techniques. Relaxation-based solution\nNMR spectroscopic investigations suggest a weak interaction with TIA1\ncondensates and indicated a reduction in the dynamics of K19 within\nthese TIA1 condensates. In contrast, a significant interaction was\nobserved between K19, and TIA1-LCD fibrils primarily mediated through <sup>321</sup>KCGS<sup>324</sup> and <sup>306</sup>VQIVYKPVDLSKV<sup>317</sup>. Our findings emphasize that the interaction between Tau and TIA1\nvaries depending on whether TIA1 is in its physiological condensate\nform or its pathological fibril state.