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Structure and dynamics of the Huntingtin exon-1 N-terminus: A solution NMR perspective

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cris.lastimport.scopus2024-02-12T19:34:04Z
dc.abstract.enMany neurodegenerative diseases are characterized by misfolding and aggregation of an expanded polyglutamine tract (polyQ). Huntington’s Disease, caused by expansion of the polyQ tract in exon 1 of the Huntingtin protein (Htt), is associated with aggregation and neuronal toxicity. Despite recent structural progress in understanding the structures of amyloid fibrils, little is known about the solution states of Htt in general, and about molecular details of their transition from soluble to aggregation-prone conformations in particular. This is an important question, given the increasing realization that toxicity may reside in soluble conformers. This study presents an approach that combines NMR with computational methods to elucidate the structural conformations of Htt Exon 1 in solution. Of particular focus was Htt’s N17 domain sited N-terminal to the polyQ tract, which is key to enhancing aggregation and modulate Htt toxicity. Such in-depth structural study of Htt presents a number of unique challenges: the long homopolymeric polyQ tract contains nearly identical residues, exon 1 displays a high degree of conformational flexibility leading to a scaling of the NMR chemical shift dispersion, and a large portion of the backbone amide groups are solvent-exposed leading to fast hydrogen exchange and causing extensive line broadening. To deal with these problems, NMR assignment was achieved on a minimal Htt exon 1, comprising the N17 domain, a polyQ tract of 17 glutamines, and a short hexameric polyProline region that does not contribute to the spectrum. A pH titration method enhanced this polypeptide’s solubility and, with the aid of ≤5D NMR, permitted the full assignment of N17 and the entire polyQ tract. Structural predictions were then derived using the experimental chemical shifts of the Htt peptide at low and neutral pH, together with various different computational approaches. All these methods concurred in indicating that low-pH protonation stabilizes a soluble conformation where a helical region of N17 propagates into the polyQ region, while at neutral pH both N17 and the polyQ become largely unstructured—thereby suggesting a mechanism for how N17 regulates Htt aggregation.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorFrydman, Judith
dc.contributor.authorShen, Konig
dc.contributor.authorJoachimiak, Lukasz A.
dc.contributor.authorFrydman, Lucio
dc.contributor.authorŻerko, Szymon
dc.contributor.authorBaias, Maria
dc.contributor.authorSmith, Pieter E.S.
dc.contributor.authorKoźmiński, Wiktor
dc.date.accessioned2024-01-26T08:21:55Z
dc.date.available2024-01-26T08:21:55Z
dc.date.issued2017
dc.description.financeNie dotyczy
dc.description.number3
dc.description.volume139
dc.identifier.doi10.1021/JACS.6B10893
dc.identifier.issn0002-7863
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/120915
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofJournal of the American Chemical Society
dc.relation.pages1168–1176
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleStructure and dynamics of the Huntingtin exon-1 N-terminus: A solution NMR perspective
dc.typeJournalArticle
dspace.entity.typePublication