The Disparate Effects of two Molecular Chaperones on Tau Amyloid Formation

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Tau is an intrinsically disordered protein that binds microtubules and plays important roles in axonal transport and microtubule stability in neurons. It has been implicated in a set of neurodegenerative diseases collectively termed tauopathies, characterized by the dissociation of tau from microtubules and its accumulation in pathological, insoluble amyloid-type aggregates. Molecular chaperones are important players in all amyloid diseases, including tauopathies, as they are part of the cellular response to prevent protein misfolding and aggregation. Tau has been shown to interact with numerous chaperones, although much of the previous work is biological in nature and few interactions have been characterized quantitatively at the molecular level. We seek to better define the interactions between tau and two heat shock proteins, Hsc70 and HSPB1. While both proteins act to prevent tau aggregation and likely play protective roles in tauopathies, their mechanisms of action are distinct. Hsc70 is a 71 kDa ATPase that uses the energy of ATP hydrolysis to assist client proteins to fold to their native structures. In contrast, HSPB1 is a 27 kDa small heat shock protein that forms large, heterogeneous oligomers and functions as a holdase, binding improperly-folded proteins and preventing aggregation. Using NMR spectroscopy, electron microscopy, fluorescence correlation spectroscopy, and other biophysical tools, we characterized the modes by which each protein binds tau and the effects of each protein on the kinetics of tau fibril formation. We show that each protein binds the aggregation-prone microtubule binding repeat region of tau, but they recognize distinct sequences within this region. In addition, the two chaperone proteins have inhibitory effects on fibril formation, but HSPB1 acts primarily during the nucleation phase of fibril formation, whereas Hsc70 has a greater effect on fibril elongation.