Two motifs within the tau microtubule-binding domain mediate its association with the hsc70 molecular chaperone.
Tau, a microtubule-associated protein with multiple phosphorylation sites, forms aggregates that correlate with neurodegeneration in Alzheimer's disease and several other neurodegenerative diseases, termed tauopathies. Hsc70 is a highly expressed constitutive chaperone 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, without an absolute requirement for tau phosphorylation. Binding requires a carboxy-terminal region of hsc70 comprising its peptide-binding and variable domains. We have identified two hsc70 binding sites on tau and hydrophobic amino acids crucial for hsc70 binding. Interestingly, these hsc70 binding sites correspond to the beta-structure elements that have been previously reported to facilitate tau aggregation. Thus, it is possible that hsc70 binding might directly inhibit tau-tau interactions that precede tau oligomerization and aggregation. Our results provide an important stimulus for research into how the hsc70-tau interaction might affect tau fate in normal cells and in disease.
Sarkar
Mitul
M
Program in Neuroscience and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Kuret
Jeff
J
Lee
Gloria
G
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D019556:COS Cells; D002417:Cattle; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008870:Microtubules / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D016875:tau Proteins