Effects of Sequence Reversal on the Conformational Dynamics, Phase Transitions, and Function of Tau Protein

Sequence reversal has been shown to significantly alter the folding and function of ordered proteins. Compared to ordered proteins, the conformations of intrinsically disordered proteins (IDPs) are more dynamic and expanded. Whether the equilibrium properties and functions of IDPs are more tolerant of sequence reversal remains unclear. In this work, we used the microtubule-associated protein Tau as a prototype IDP and investigated the effects of sequence reversal on its equilibrium conformation, phase transitions, and function. We found that the sequence-reversed protein behaved like an IDP, with the similar level of conformational expansion, dynamics, and secondary structure content as its parent protein. Our analysis revealed that the dynamic non-specific electrostatic interactions were not markedly perturbed upon sequence reversal, enabling the sequence-reversed protein to undergo liquid-liquid phase separation as its parent does. On the contrary, our results showed that sequence reversal disrupted residue-specific interactions. Thus, the sequence-reversed protein could not aggregate into amyloid fibrils or assist in microtubule assembly. Taken together, our findings indicate that sequence reversal could have distinct effects on the conformational dynamics, phase transitions, and function of IDPs.