Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble

PloS One
Shaolong ZhuDerek J Wilson

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...Continue Reading

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Citations

Mar 12, 2016·Journal of the American Society for Mass Spectrometry·Shaolong ZhuDerek J Wilson
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Jul 28, 2020·Biomedicines·Dominic NarangDerek J Wilson
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Methods Mentioned

BETA
X-ray
NMR
by
chip
chips
FRET

Software Mentioned

MMTSB
ASA
MS
Sphere
VersaLaser
VADAR
HDX
FRODAN
FORTRAN
TRESI

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