1. The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity
- Author
-
Carlos A. Elena-Real, Amin Sagar, Annika Urbanek, Matija Popovic, Anna Morató, Alejandro Estaña, Aurélie Fournet, Christine Doucet, Xamuel L. Lund, Zhen-Dan Shi, Luca Costa, Aurélien Thureau, Frédéric Allemand, Rolf E. Swenson, Pierre-Emmanuel Milhiet, Ramon Crehuet, Alessandro Barducci, Juan Cortés, Davy Sinnaeve, Nathalie Sibille, Pau Bernadó, Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Équipe Robotique et InteractionS (LAAS-RIS), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Institut Laue-Langevin (ILL), National Institutes of Health [Bethesda] (NIH), Beamline SWING, Synchrotron SOLEIL, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Institute for Advanced Chemistry of Catalonia, Biologie Structurale Intégrative (ERL 9002 - BSI ), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), ANR-17-CE11-0022,GPCteR,Mécanismes moléculaires des régions C-terminales désordonnées et fonctionnelles des RCPG et impact sur les voies de la signalisation cellulaire dépendantes de l'arrestine(2017), ANR-19-P3IA-0004,ANITI,Artificial and Natural Intelligence Toulouse Institute(2019), European Project: 648030,H2020,ERC-2014-CoG,chemREPEAT(2015), and European Commission
- Subjects
Huntington’s disease is a neurodegenerative disorder ,poly-Q-related diseases ,Pathogenic huntingtin ,Structural Biology ,[SDV]Life Sciences [q-bio] ,Proteins ,Protein aggregation ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,HTT gene ,Solution-state NMR ,Molecular Biology - Abstract
Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended polyglutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due to its intrinsic flexibility and the strong compositional bias. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines. Integrative data analysis reveals that the poly-Q tract adopts long α-helical conformations propagated and stabilized by glutamine side chain to backbone hydrogen bonds. We show that α-helical stability is a stronger signature in defining aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. Our observations provide a structural perspective of the pathogenicity of expanded httex1 and pave the way to a deeper understanding of poly-Q-related diseases., We thank G. Otting (Australian National University, Canberra, Australia) for providing the BL21 (DE3) Star::RF1-CBD3 strain. This work was supported by the European Research Council under the European Union’s H2020 Framework Programme (2014–2020)/ERC grant agreement no. 648030 and Labex EpiGenMed, an Investissements d’avenir program (grant no. ANR-10-LABX-12-01) awarded to P.B., grant no. ANR-17-CE11-0022-01 awarded to N.S. and grant no. ANR-19-PI3A-0004 awarded to J.C. The Centre for Structural Biology (CBS) is a member of France-BioImaging (FBI) and the French Infrastructure for Integrated Structural Biology, two national infrastructures supported by the French National Research Agency (grant nos. ANR-10-INBS-04-01 and ANR-10-INBS-05, respectively). A.U. is supported by a grant from the Fondation pour la Recherche Médicale (grant no. SPF20150934061). D.S. acknowledges a grant from the Métropole Européenne de Lille (PUSHUP). G. Levy (Université de Lille) is thanked for help with sample preparation and the 19F-NMR experiments. This work benefited from the high-performance computing resources of CSUC and the CALMIP supercomputing center under the allocations 2016-P16032 and 2021-P21043. The 600 MHz spectrometer for 19F-NMR measurements is funded by the Nord Region Council, CNRS, Institut Pasteur de Lille, the European Community (European Regional Development Fund, ERDF), the French Ministry of Research and the Université de Lille and by the CTRL CPER cofunded by the European Union with the ERDF, by the Hauts-de-France Regional Council (contract no. 17003781), Métropole Européenne de Lille (contract no. 2016_ESR_05) and the French State (contract no .2017-R3-CTRL-Phase1). We thank the SWING beamline at the SOLEIL synchrotron, Saint-Aubin, France (proposal 20181386), and P12 beamline at PETRAIII, Hamburg, Germany, for beamtime allocation to the project and assistance during data collection.
- Published
- 2023