Probing initial transient oligomerization events facilitating Huntingtin fibril nucleation at atomic resolution by relaxation-based NMR

Proceedings of the National Academy of Sciences of the United States of America
Samuel A KotlerG Marius Clore

Abstract

The N-terminal region of the huntingtin protein, encoded by exon-1, comprises an amphiphilic domain (httNT), a polyglutamine (Q n ) tract, and a proline-rich sequence. Polyglutamine expansion results in an aggregation-prone protein responsible for Huntington's disease. Here, we study the earliest events involved in oligomerization of a minimalistic construct, httNTQ7, which remains largely monomeric over a sufficiently long period of time to permit detailed quantitative NMR analysis of the kinetics and structure of sparsely populated [Formula: see text] oligomeric states, yet still eventually forms fibrils. Global fitting of concentration-dependent relaxation dispersion, transverse relaxation in the rotating frame, and exchange-induced chemical shift data reveals a bifurcated assembly mechanism in which the NMR observable monomeric species either self-associates to form a productive dimer (τex ∼ 30 μs, Kdiss ∼ 0.1 M) that goes on to form a tetramer ([Formula: see text] μs; Kdiss ∼ 22 μM), or exchanges with a "nonproductive" dimer that does not oligomerize further (τex ∼ 400 μs; Kdiss ∼ 0.3 M). The excited state backbone chemical shifts are indicative of a contiguous helix (residues 3-17) in the productive dimer/tetramer, with...Continue Reading

References

Apr 1, 1995·Nature Structural Biology·G M CloreA M Gronenborn
Aug 12, 2004·Chemical Reviews·Arthur G Palmer
Apr 15, 2006·Science·Anthony Mittermaier, Lewis E Kay
Nov 7, 2006·Journal of Magnetic Resonance·Junji IwaharaG Marius Clore
Apr 10, 2007·Annual Review of Neuroscience·Harry T Orr, Huda Y Zoghbi
Aug 28, 2009·The Journal of Biological Chemistry·Charity T AikenJ Lawrence Marsh
Jul 29, 2010·Physiological Reviews·Chiara ZuccatoElena Cattaneo
Feb 15, 2011·Nature Structural & Molecular Biology·Karunakar KarRonald Wetzel
Mar 9, 2011·Journal of the American Chemical Society·V N SivanandamPatrick C A van der Wel
Jul 19, 2011·Journal of Molecular Biology·Robert SchneiderMarc Baldus
Nov 15, 2011·The Journal of Physical Chemistry. B·Pramodh VallurupalliLewis E Kay
Feb 7, 2012·Journal of Molecular Biology·Ronald Wetzel
Mar 13, 2012·Annual Review of Physical Chemistry·Gunnar Jeschke
Jan 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kirupa SathasivamGillian P Bates
Nov 28, 2013·Proceedings of the National Academy of Sciences of the United States of America·Scott L CrickRohit V Pappu
Feb 25, 2015·Quarterly Reviews of Biophysics·Nicholas J Anthis, G Marius Clore
Mar 6, 2015·Biomolecular Concepts·James R ArndtJustin Legleiter
Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Cody L HoopPatrick C A van der Wel
Mar 5, 2016·Neuron·Frédéric Saudou, Sandrine Humbert
Jan 1, 2015·Nature Reviews. Disease Primers·Gillian P BatesSarah J Tabrizi
Jul 22, 2016·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Thomas SchmidtG Marius Clore
Jan 14, 2017·Journal of the American Chemical Society·Maria BaiasLucio Frydman
Aug 3, 2017·Protein Science : a Publication of the Protein Society·Charles D SchwietersG Marius Clore
Oct 14, 2018·The Journal of Biological Chemistry·Jose M Bravo-ArredondoRalf Langen

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Citations

May 3, 2019·Nature Communications·Albert EscobedoXavier Salvatella
Aug 17, 2019·Journal of Neurochemistry·Erich E WankerSigrid Schnoegl
Oct 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Theodoros K KaramanosG Marius Clore
Jul 23, 2020·Journal of Biomolecular NMR·Ved Prakash Tiwari, Pramodh Vallurupalli
Mar 5, 2020·Proceedings of the National Academy of Sciences of the United States of America·Alberto CecconG Marius Clore
Nov 22, 2020·Biophysical Chemistry·Emma E CawoodSheena E Radford
Jan 14, 2021·Analytical Chemistry·Yunfei HuMaili Liu
Aug 18, 2020·Chembiochem : a European Journal of Chemical Biology·Anass ChikiHilal A Lashuel
Feb 25, 2021·Journal of Neurology·Melanie Alpaugh, Francesca Cicchetti
Mar 2, 2021·Chembiochem : a European Journal of Chemical Biology·Marielle A WältiG Marius Clore
Dec 14, 2019·Current Opinion in Structural Biology·T Reid Alderson, Lewis E Kay
May 6, 2021·Current Opinion in Structural Biology·H Jane Dyson, Peter E Wright
May 8, 2021·Royal Society Open Science·Emilie N LiuZhefeng Guo
Jun 22, 2021·Current Opinion in Structural Biology·Sara Linse
Jul 3, 2021·International Journal of Molecular Sciences·Arnaud MarquetteBurkhard Bechinger
Sep 3, 2021·The Journal of Physical Chemistry. B·Muhammed Shafeek Oliyantakath HassanVinesh Vijayan

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