The molecular mechanism of Hsp90-induced oligomerization of Tau

Abstract

Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer's disease with Tau oligomers suspected as the most toxic agent. Tau is a client of Hsp90, though it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, though 'paper-clip'-shaped by long-range contacts. Interaction with Hsp90 promotes an open Tau conformation, which we identify as the molecular basis for the formation of small Tau oligomers by exposure of the aggregation-prone repeat domain to other Tau molecules. At the same time, formation of Tau fibrils is inhibited. We therefore provide the nanometer-scale zoom into chaperoning an amyloid client, highlighting formation of oligomers as the consequence of this biologically relevant interaction.

Chaperoning shape-shifting tau in disease

“…The JDP and Hsp70 chaperone families are responsible for targeting and partially refolding tau, respectively, but these interactions are insufficient to return tau to a nonpathological state. It has been proposed that Hsp90 coordinates with Hsp70 to bind to the RD and revert tau to an inert form [84][85][86], but important questions remain as to how Hsp90 influences tau assembly and how Hsp90 cochaperones are involved. Hsp90 is a 'split-ATPase', where the catalytic residues that hydrolyze ATP are 'split' between two domains [87,88].…”

“…Hsp90 can then bind to the tau:Hsp70 complex and complete the refolding of tau along the RDs, thus burying some of the hydrophobic surfaces and generating an inert monomer of tau [84]. However, recent data suggest that Hsp90 binding to tau may stabilize aggregation-prone conformations by exposing other amyloidogenic hydrophobic motifs [86]. Indeed, cell and animal experiments suggest that Hsp90 may cooperate with chaperones to promote tau pathology [90].…”