Conformational heterogeneity of tau: Implication on intrinsic disorder, acid stability and fibrillation in Alzheimer's disease.

The self-assembly of intrinsically disordered protein tau into paired helical filament forms one of the hallmarks of Alzheimer's disease. However, the facets of innately disordered structure of tau and its conversion to a β-sheet-rich fibril during several tauopathies are poorly understood. Here, we provide a direct insight into the ensemble of highly heterogeneous conformational families of tau at physiological pH, by nano-electrospray mass spectrometry coupled with ion mobility. The average collision cross section of the most unfolded conformer was higher by >2 fold than that of the most folded one. Acidic pH largely induced unfolding in tau, obliterating the compact conformers completely. The highly unfolded conformers were the key species bestowing the unusual solubility to tau at low pH, with limited contribution from intramolecular long-range interfaces giving rise to ordered conformers. Contrarily, alkaline pH shifted tau towards folded conformations due to charge neutralization, keeping the overall random coil architecture intact. Intriguingly, the heparin-induced in vitro aggregation propensity of the protein attenuated at both acidic and alkaline pH, illustrating the significance of altered conformations in pathological functions of tau. Our observations at low pH indicate that a reorganization of the intricate network of momentary long-range contacts in tau might have implication in its aggregation pathology. Disease-modifying therapies for Alzheimer's disease targeting either to disrupt the essential fibril-forming interaction at third microtubule-binding repeat of tau or to perturb specific binding interaction of tau with endogenous polyanionic species might be of high benefit.