Abstract
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.
Highlights
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp[70] inhibits the aggregation of the amyloid protein tau
The inhibitory action on tau aggregation by Hsp[70] was found to be independent of ATP/ADP and cochaperones.[10−12]. It is not known which molecular steps of tau aggregation are inhibited by Hsp[70] and which tau species are targeted by the chaperone
A sedimentation assay was used to measure the relative levels of insoluble K18 ΔK280 tau formed at increasing Hsp[70] concentrations
Summary
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp[70] inhibits the aggregation of the amyloid protein tau. The aberrant aggregation of tau into intracellular deposits is thought to play a key role in the pathogenesis of various human tauopathies including Alzheimer’s disease (AD).[1] During disease, tau forms large intracellular aggregates termed neurofibrillary tangles, and their abundance and localization in the brain correlates with cognitive decline.[2,3] As part of the quality control machinery of the cell, molecular chaperones such as the highly abundant heat shock protein 70 (Hsp70) counteract the aggregation of amyloid proteins and target misfolded species for degradation.[4]. It is not known which molecular steps of tau aggregation are inhibited by Hsp[70] and which tau species are targeted by the chaperone This is partly owed to the difficulty of studying protein aggregates as they are highly heterogeneous in nature and can populate rare and transient species such as small soluble oligomers. Our results show how the chaperone Hsp[70] counteracts the formation, propagation, and toxicity of tau aggregates
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