Tau local structure shields amyloid motif and controls aggregation propensity

Abstract

33These local structural rearrangements provide a biophysical framework supporting a model in which 34perturbations initiate early events in sporadic and genetic tau pathogenesis.

Hsp40s play complementary roles in the prevention of tau amyloid formation

“…In the presence of HSPB1 and DNAJA2, the resulting binding profiles of the two tau variants were very similar to those of wild-type tau, with residues 274-280 and 305-318, corresponding to PHF6* and PHF6 repeats, displaying severe peak broadening (Figure 4C and Figure 4 figure supplement 4A). This similarity to wild-type tau was not unexpected, though, as only a small portion of the P301L/S tau conformational ensemble adopts the extended conformation at any given moment (48,57). In contrast, DNAJB1, while showing no binding to wild-type tau, did cause noticeable reductions in peak intensities in both PHF6 motifs of the P301S and P301L tauopathy mutants (Figure 4C and Figure 4 figure supplement 4A).…”

“…A clue to how heparin alters the conformational ensemble of tau 4R came from a recent structural characterization of patient-derived, seeding-competent tau monomer. This species of tau was reported to have an expanded ensemble with a more exposed PHF6 motif compared to the inert monomeric protein (47,48). This increased expansion of the PHF6 aggregation motifs was, in turn, suggested to drive the self-assembly and subsequent aggregation of tau (53).…”

“…The effect of DNAJB1 on tau 4R nucleation, despite its inability to interact with monomeric tau 4R , can, however, be reconciled by the recent finding that soluble monomeric tau 4R exists in two conformational ensembles -an ensemble that does not spontaneously aggregate ("inert" tau monomer) and a seedcompetent monomer that triggers the spontaneous aggregation of tau (47,48). It is therefore possible that DNAJB1 only identifies and interacts with the "aggregation-prone" tau species and not the inert monomers.…”

“…Such seed-competent species have been proposed to be readily populated in tauopathy-associated tau mutants (48), and can be generated in vitro by addition of polyanions such as heparin (49). Unfortunately, the addition of heparin causes the rapid formation of tau fibers, thus preventing a detailed structural investigation of the seed-competent ensemble using NMR spectroscopy.…”

“…To further test whether the expansion of the PHF6 repeats in the seeding-competent tau species is indeed the discriminating factor for chaperone binding, we monitored the interaction of the three chaperones with P301L/S missense mutations, which are known to cause dominantly inherited tauopathy (56). These tau variants had been shown to contain a higher population of the expanded PHF6 conformation (48), as also seen in our RDC measurements (Figure 4 figure supplement 3D and 3E), and could therefore potentially mimic the aggregation-prone tau without requiring the addition of heparin.…”