| Tau, a microtubule-associated protein with a complex and dynamic phosphorylation profile, forms fibrillar aggregates that correlate with neuronal death in Alzheimer Disease and several other neurodegenerative diseases, termed tauopathies. Hsc70 is a constitutively-expressed ubiquitous molecular chaperone of the HSP70 family that can drive conformational change in proteins, prevent the aggregation of its substrates, recognize misfolded substrates and facilitate their degradation. Here, we show that hsc70 binds to the microtubule-binding domain of tau in vitro and in vivo. Tau phosphorylation is not required for hsc70 binding. Binding requires a carboxy-terminal region of hsc70 comprising its peptide-binding domain and a part of its variable domain. The ATPase activity of hsc70 is not required for binding tau. We also show that hsc70 is capable of binding tau that is not associated with microtubules. We identify two hsc70-binding sites on tau and demonstrate that hydrophobic amino acids present at both sites are crucial for the binding of hsc70 as well as the inducible chaperone, hsp70. Interestingly, these hsc70/hsp70-binding sites closely overlap the beta-structure sequences that have been previously reported to facilitate tau aggregation. Thus, hsc70tau binding may be expected to directly inhibit tau-tau interactions that precede tau oligomerization and aggregation. Our results provide an important stimulus for research into how tau interactions with hsc70, hsp70 and other molecular chaperones might affect tau metabolism in normal cells and in disease. |
