DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation

Abstract

Molecular chaperones, including Hsp70/J-domain protein (JDP) families, play central roles in binding substrates to prevent their aggregation. How JDPs select different conformations of substrates remains poorly understood. Here, we report an interaction between the JDP DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a β-turn structural element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau, but not mutant, β-turn structural elements can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. Our work identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.

UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome

“…Chaperone complexes, which engage with folded substrates, have also been observed in other biological pathways. For example, a specific J-domain protein was shown to bind natively folded tau in order to prevent protein aggregation 46 . Intriguingly, Tyr582 of the myosin FX 3 HY-motif has to fulfill two critical functions.…”

DnaJC7 specifically regulates tau seeding

“…DnaJC7 rescue experiments to test 17 known ALS-associated missense mutations revealed that the T341P mutant recapitulated the seeding profile of the DnaJC7 (HPQ) mutant incapable of binding to Hsp70. The T341P mutation is in the TPR2B domain, which we have previously found to be the main site of tau binding on DnaJC7 15 . Additionally, rescue with the two J domain mutants (R412W and R425K) increased seeding relative to the WT DnaJC7 sequence, but both mutants still seeded lower than the T341P and HPQ mutants.…”

“…We have previously reported that DnaJC7 preferentially bound natively folded tau monomer vs. seed-competent monomer or aggregation-prone mutants 15 . In this study, DnaJC7 KO alone increased tau seeding for all seed sources tested, suggesting an interaction with endogenous tau with a mechanism independent of seed conformation.…”

Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation

“…Interestingly, recent work shows that, while DnaJA2, DnaJB1, and Hsc70 all bind to the same tau region, Hsc70 binds preferentially to the monomeric tau, DnaJB1 binds to the oligomerized form, and DnaJA2 binds to both ( 124 ). Another recent proteomic study revealed that DnaJC7 is yet another cochaperone that interacts with tau ( 125 ). In this case, the cochaperone specifically binds with higher affinity to the natively folded tau, and this interaction is thought to stabilize the native conformation to prevent aggregation.…”