title: Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble.
abstract: Tau is an intrinsically disordered protein (IDP) whose primary physiological role is to stabilize microtubules in neuronal axons at all stages of development. In Alzheimer's and other tauopathies, tau forms intracellular insoluble amyloid aggregates known as neurofibrillary tangles, a process that appears in many cases to be preceded by hyperphosphorylation of tau monomers. Understanding the shift in conformational bias induced by hyperphosphorylation is key to elucidating the structural factors that drive tau pathology, however, as an IDP, tau is not amenable to conventional structural characterization. In this work, we employ a straightforward technique based on Time-Resolved ElectroSpray Ionization Mass Spectrometry (TRESI-MS) and Hydrogen/Deuterium Exchange (HDX) to provide a detailed picture of residual structure in tau, and the shifts in conformational bias induced by hyperphosphorylation. By comparing the native and hyperphosphorylated ensembles, we are able to define specific conformational biases that can easily be rationalized as enhancing amyloidogenic propensity. Representative structures for the native and hyperphosphorylated tau ensembles were generated by refinement of a broad sample of conformations generated by low-computational complexity modeling, based on agreement with the TRESI-HDX profiles.
authors.affiliation: Chemistry Department, York University, Toronto, ON, Canada.
authors.forename: Shaolong
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Chemistry Department, York University, Toronto, ON, Canada.
authors.forename: Agnesa
authors.initials: A
authors.lastname: Shala
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Bezginov
authors.affiliation: Department of Physics, Ryerson University, Toronto, ON, Canada.
authors.forename: Adnan
authors.initials: A
authors.lastname: Sljoka
authors.affiliation: Chemistry Department, York University, Toronto, ON, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Audette
authors.affiliation: Chemistry Department, York University, Toronto, ON, Canada; Center for Research in Mass Spectrometry, Faculty of Science, York University, Toronto, ON, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Wilson
mesh_terms: D041961:Deuterium Exchange Measurement; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D024801:Tauopathies / Q000473:pathology*; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D064267:Intrinsically Disordered Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3