Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.
Sue-Ann MokCarlo CondelloRebecca FreilichAnne GilliesTaylor ArharJavier OrozHarindranath KadavathOlivier JulienVictoria A AssimonJennifer N RauchBryan M DunyakJungsoon LeeFrancis T F TsaiMark R WilsonMarkus ZweckstetterChad A DickeyJason E GestwickiPublished in: Nature structural & molecular biology (2018)
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.
Keyphrases
- cerebrospinal fluid
- heat shock
- endothelial cells
- induced pluripotent stem cells
- copy number
- physical activity
- heat shock protein
- pluripotent stem cells
- gene expression
- high resolution
- molecular dynamics simulations
- dna methylation
- human immunodeficiency virus
- small molecule
- cross sectional
- anti inflammatory
- bone mineral density
- hiv infected
- hiv testing
- amino acid
- data analysis