Degree Granting Department
Biology (Cell Biology, Microbiology, Molecular Biology)
Gary W. Daughdrill
aggregation, Alzheimer's, chaperone, disorder, tangles, tau
The accumulation of the microtubule associated protein tau has been implicated in several neurological disorders; however, its interaction with chaperones along its normal degradation pathway remains largely uncharacterized at single residue resolution. In this study, nuclear magnetic resonance (NMR) spectroscopy was used to probe the interaction between tau, the molecular chaperone Hsp90, and the immunophilin FKBP51. Resonance intensity changes were observed for specific residues in the heteronuclear single quantum coherence (HSQC) spectra of 15N-labeled tau in the presence of Hsp90 and/or FKBP51. Analysis of the HSQC spectra identified the two hydrophobic hexapeptide motifs located at residues V275 - K280 and V306 - K311 in tau's C-terminal assembly domain as the sites of an interaction with both Hsp90 and FKBP51. Resonances that show reduced intensities did not experience line broadening, which suggests that slow chemical exchange is occurring with a bound conformation that is not observable due to the molecular weight of the complex. We have also investigated the role of the PPIase domain alone in binding to tau and found that specific residues within the PPIase active site experience significant reductions in intensity upon addition of tau. The experimental data is collectively used to propose a structural model for ternary complex formation between tau, Hsp90, and FKBP51.
Scholar Commons Citation
Barrett, Alexander Steven, "Structural Basis for Ternary Complex Formation Between tau, Hsp90, and FKBP51" (2013). Graduate Theses and Dissertations.