HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

Abstract

The microtubule-associated protein tau forms insoluble, amyloid-type aggregates in various dementias, most notably Alzheimer's disease. Cellular chaperone proteins play important roles in maintaining protein solubility and preventing aggregation in the crowded cellular environment. While tau is known to interact with numerous chaperones, it remains unclear how these chaperones function mechanistically to prevent tau aggregation and how chaperones from different classes compare in terms of mechanism. Here, we focused on the small heat shock protein HspB1 and the constitutive chaperone Hsc70 (also known as HspA8), and report how each chaperone interacts with tau to prevent its fibril formation. Using fluorescence and NMR spectroscopy, we show that the two chaperones inhibit tau fibril formation by distinct mechanisms. HspB1 delayed tau fibril formation by weakly interacting with early species in the aggregation process, while Hsc70 was highly efficient at preventing tau fibril elongation possibly by capping the ends of tau fibrils. Both chaperones recognized aggregation-prone motifs within the microtubule-binding repeat region of tau. However, HspB1 binding remained transient in both aggregation-promoting and nonaggregating conditions, whereas Hsc70 binding was significantly tighter under aggregationpromoting conditions. These differences highlight the fact that chaperones from different families play distinct but complementary roles in the prevention of pathological protein aggregation.

Shedding light on aberrant interactions – a review of modern tools for studying protein aggregates

“…This study showed that Hsp70 slows down the nucleation process of tau, stabilises oligomeric species and inhibits their growth into fibrils . Similar findings were made in a second study, comparing the action of Hsp70 and a second chaperone, HspB1, on K18 and full‐length tau aggregation using FCS and NMR .…”

Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3

“…A 3.4-Å resolution cryo-electron microscopy structure of the common protofilament core of tau filaments purified from an individual with Alzheimer’s disease (PDB ID 5O3L) shows a 306-VQI-308 motif at the start of the first ordered beta sheet [60]. Recent NMR data revealed HspB1 to interact with this region of tau, consistent with binding of substrate IXI/V motifs to sHsp β4/β8 pockets [61]. In such a mechanism of sHsp chaperone action, activity towards these fibril-forming sequences will be modulated by the structural dynamics of both sHsp assembly and the substrate.…”

Local unfolding of the HSP27 monomer regulates chaperone activity

“…It is possible that the same mechanism for rapid, promiscuous recognition of binding partners by IDPs is responsible for the heightened activity of partially unfolded chaperones. Recent reports have indicated that HSP27 interacts with substrates αsynuclein and Tau in a dynamic, transient manner 64,65 with CSPs induced by Tau binding identified in the β6 + 7 strand of cHSP27 65 . Interestingly, many of the residues that are unfolded in the HSP27 monomer are charged or polar (Fig.…”