The protein-surfactant stoichiometry governs the conformational switching and amyloid nucleation kinetics of tau K18.

Amyloids are pathological hallmarks of a number of debilitating neurodegenerative diseases. Understanding the molecular mechanism of protein amyloid assembly with an emphasis on structural characterization of early, key prefibrillar species is important for targeted drug design and clinical interventions. Tau is an intrinsically disordered, microtubule-binding protein which is also implicated in various neurodegenerative disorders such as frontotemporal dementia, Down's syndrome, Alzheimer's disease, etc. Earlier reports have demonstrated that tau aggregation in vitro is triggered by anionic inducers, presumably due to charge compensation which facilitates intermolecular association between the tau polypeptide chains. However, the molecular mechanism of tau amyloid aggregation, involving the structural characterization of amyloidogenic intermediates formed especially during early key steps, remains elusive. In this work, we have employed a spectroscopic toolbox to elucidate the mechanism of anionic surfactant-induced disorder-to-order amyloid transition of a tau segment. This study revealed that the amyloid assembly is mediated via binding-induced conformational switching into an early partially helical amyloid-competent intermediate. Additionally, protein and inducer concentration-dependent studies indicated that at the higher protein and/or inducer concentrations, competing off-pathway intermediates dampen the amyloid assembly which implies that the stoichiometry of protein and inducer plays a key regulatory role in the amyloid nucleation and fibril elongation kinetics.