Mapping interactions with the chaperone network reveals factors that protect against tau aggregation

Nat Struct Mol Biol. 2018 May;25(5):384-393. doi: 10.1038/s41594-018-0057-1. Epub 2018 Apr 30.


A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • HSP40 Heat-Shock Proteins / metabolism*
  • Humans
  • Protein Aggregates / physiology
  • Protein Aggregation, Pathological / prevention & control*
  • Protein Binding / physiology
  • tau Proteins / metabolism*


  • DNAJA2 protein, human
  • HSP40 Heat-Shock Proteins
  • MAPT protein, human
  • Protein Aggregates
  • tau Proteins