Competitive inclusion of chloro-substituted acetic acids into β-cyclodextrin monitored by rotational correlation frequencies of 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxy radical

Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer's disease with Tau oligomers suspected as the most toxic agent. Tau is a client of the molecular chaperone Hsp90, although it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, although "paper clip"-shaped by long-range contacts. Interaction with Hsp90 promotes an open Tau conformation, which we identify as the molecular basis for the formation of small Tau oligomers by exposure of the aggregation-prone repeat domain to other Tau molecules. At the same time, formation of Tau fibrils is inhibited. We therefore provide the nanometer-scale zoom into chaperoning an amyloid client, highlighting formation of oligomers as the consequence of this biologically relevant interaction.

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“…The spectra were analyzed using homewritten MATLAB scripts. Rotational correlation times  corr were obtained using Kivelson's equation (56).…”

Section: Epr Experimentsmentioning

confidence: 99%

The mechanism of Hsp90-induced oligomerizaton of Tau

et al. 2020

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“…Various stable nitroxide radicals ( 2,100,106,284,311,328,329,(333)(334)(335), and y irradia tion genera ted radicals from incorporated gues ts ( 4-,5,7 ], have been studied in great number by electron spin resonance spectroscopy. The 'H-NMR spectra of stable nitroxide radical spin labels showed enhanced relaxation of the carbohydrate proton nuclei in the vicinity of the binding site ( 330 1.…”

Section: 44- Radicalsmentioning

confidence: 99%

Cyclodextrin Inclusion Complexes

Szejtli

1988

Topics in Inclusion Science

133

134

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“…The spectra were analyzed using homewritten Matlab scripts. Rotational correlation times τcorr were obtained using Kivelson's equation (56). DEER measurements were performed at Q-band frequency at 50 K with a sample volume of 12.5 l.…”

Section: Protein Expression and Spin Labelingmentioning

confidence: 99%

The molecular mechanism of Hsp90-induced oligomerization of Tau

Weickert

Wawrzyniuk

John

et al. 2019

Preprint

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Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer's disease with Tau oligomers suspected as the most toxic agent. Tau is a client of Hsp90, though it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, though 'paper-clip'-shaped by long-range contacts. Interaction with Hsp90 promotes an open Tau conformation, which we identify as the molecular basis for the formation of small Tau oligomers by exposure of the aggregation-prone repeat domain to other Tau molecules. At the same time, formation of Tau fibrils is inhibited. We therefore provide the nanometer-scale zoom into chaperoning an amyloid client, highlighting formation of oligomers as the consequence of this biologically relevant interaction.

show abstract

Competitive inclusion of chloro-substituted acetic acids into β-cyclodextrin monitored by rotational correlation frequencies of 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxy radical

Cited by 13 publications

References 7 publications

The mechanism of Hsp90-induced oligomerizaton of Tau

The mechanism of Hsp90-induced oligomerizaton of Tau

Cyclodextrin Inclusion Complexes

The molecular mechanism of Hsp90-induced oligomerization of Tau

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