Spontaneous Rupture and Entanglement of Human Neuronal Tau Protein Induced by Piconewton Compressive Force

Mechanical force vector fluctuations in living cells can have a significant impact on protein behavior and functions. Here we report that a human tau protein tertiary structure can abruptly and spontaneously rupture, like a balloon, under biologically available piconewton compressive force, using a home-modified atomic force microscopy single-molecule manipulation. The rupture behavior is dependent on the physiological level of presence of ions, such as K⁺ and Mg²⁺. We observed rupture events in the presence of K⁺ but not in the presence of Mg²⁺ ions. We have also explored the entangled protein state formed following the events of the multiple and simultaneous protein ruptures under crowding. Crowded proteins simultaneously rupture and then spontaneously refold to an entangled folding state, different from either folded and unfolded states of the tau protein, which can be a plausible pathway for the tau protein aggregation that is related to a number of neurodegenerative diseases.