Huntingtin's N-Terminus Rearrangements in the Presence of Membranes: A Joint Spectroscopic and Computational Perspective

ACS Chemical Neuroscience
Geraldine R LevyLucio Frydman

Abstract

Huntington's disease is a neurodegenerative disorder resulting from an expanded polyglutamine (polyQ) repeat of the Huntingtin (Htt) protein. Affected tissues often contain aggregates of the N-terminal Htt exon 1 (Htt-Ex1) fragment. The N-terminal N17 domain proximal to the polyQ tract is key to enhance aggregation and modulate Htt toxicity. Htt-Ex1 is intrinsically disordered, yet it has been postulated that under physiological conditions membranes induce the N17 to adopt an α-helical structure, which then plays a key role in regulating Htt protein aggregation. The present study leverages the recently available assignment of NMR peaks in an N17Q17 construct, in order to provide a look into the changes occurring in vitro upon exposing this fragment to various brain extract fragments as well as to synthetic bilayers. Residue-specific changes were observed by 3D HNCO NMR, whose nature was further clarified with ancillary CD and aggregation studies, as well as with molecular dynamic calculations. From this combination of measurements and computations, a unified picture emerges, whereby transient structures consisting of α-helices spanning a fraction of the N17 residues form during N17Q17-membrane interactions. These interactions a...Continue Reading

Citations

Jun 6, 2021·Biochimica Et Biophysica Acta. Biomembranes·Adewale AdegbuyiroJustin Legleiter
Jul 3, 2021·International Journal of Molecular Sciences·Arnaud MarquetteBurkhard Bechinger
Jul 12, 2021·Colloids and Surfaces. B, Biointerfaces·Sharon E GrooverJustin Legleiter
Dec 28, 2019·ACS Chemical Neuroscience·Faezeh SedighiJustin Legleiter
Dec 17, 2019·ACS Chemical Neuroscience·Sanda Nastasia Moldovean, Vasile Chiş

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