title: Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells.
abstract: Huntington's disease is caused by a CAG trinucleotide expansion mutation in the Huntingtin gene that leads to an artificially long polyglutamine sequence in the Huntingtin protein. A key feature of the disease is the intracellular aggregation of the Huntingtin exon 1 protein (Httex1) into micrometer sized inclusion bodies. The aggregation process of Httex1has been extensively studied in vitro, however, the crucial early events of nucleation and aggregation in the cell remain elusive. Here, we studied the conformational dynamics and self-association of Httex1by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation. Both short and long polyglutamine variants of Httex1underwent an apparent temperature-induced conformational collapse. The temperature jumps generated a population of kinetically trapped species selectively for the longer polyglutamine variants of Httex1proteins. Their occurrence correlated with the formation of inclusion bodies suggesting that such species trigger further self-association.
authors.affiliation: Department of Physical Chemistry II, Ruhr-University Bochum, Universitaetsstraße 150, D-44780 Bochum, Germany. Simon.Ebbinghaus@rub.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Büning
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sharma
authors.forename: Shivang
authors.initials: S
authors.lastname: Vachharajani
authors.forename: Estella
authors.initials: E
authors.lastname: Newcombe
authors.forename: Angelique
authors.initials: A
authors.lastname: Ormsby
authors.forename: Mimi
authors.initials: M
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Gnutt
authors.forename: Tobias
authors.initials: T
authors.lastname: Vöpel
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
authors.forename: Simon
authors.initials: S
authors.lastname: Ebbinghaus
mesh_terms: D000071058:Huntingtin Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000503:physiopathology; D066298:In Vitro Techniques; D002479:Inclusion Bodies / Q000378:metabolism; D007834:Lasers; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D066263:Protein Aggregation, Pathological / Q000503:physiopathology*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013696:Temperature; D014461:Ultracentrifugation
chemical_list: D000071058:Huntingtin Protein; D010455:Peptides; C097188:polyglutamine