1. Structural and molecular basis of cross-seeding barriers in amyloids
- Author
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Denis Martinez, Abdelmajid Noubhani, Loren B. Andreas, Guido Pintacuda, Benjamin Bardiaux, Brice Kauffmann, Asen Daskalov, Mélanie Berbon, Antoine Loquet, Joseph S. Wall, Virginie Coustou, Nadia El Mammeri, Jan Stanek, Sven J. Saupe, Birgit Habenstein, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre de Résonance Magnetique Nucleaire (CRMN), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brookhaven National Laboratory [Upton, NY] (BNL), UT-Battelle, LLC-Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY)-U.S. Department of Energy [Washington] (DOE), We acknowledge financial support from the European Research Council (ERC) under the European Unions Horizon 2020 Research and Innovation Programme (ERC-2015-CoG GA 648974 to G.P. and ERC-2015-StG GA 639020 to A.L.), IdEx Bordeaux (Chaire d’Installation to B.H., ANR-10-IDEX-03-02), the Agence Nationale de la Recherche (ANR) (ANR-14-CE09-0020-01 to A.L., ANR-13-PDOC-0017-01 to B.H. and ANR-17-CE11-0035 to S.J.S), the INCEPTION project (Programme d'investissements d'avenir/ANR-16-CONV-0005) and the CNRS (IR-RMN FR3050). J.S. and L.B.A. were supported by individual Marie Sklodowska-Curie incoming fellowships (grant agreements 661799 'COMPLEX-FAST-MAS' and 624918 'MEM-MAS'). A.D. was supported by the Nouvelle Aquitaine Regional Council., We thank the Nouvelle Aquitaine Regional Council, University of Bordeaux, and the Contrat Plan Etat-Region (CPER) CampusB Bordeaux for the acquisition of the NMR equipment. This work has benefited from the Biophysical and Structural Chemistry Platform at IECB, CNRS UMS 3033, INSERM US001., ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), ANR-14-CE09-0020,NanoSSNMR,Nanostructures biologiques et synthétiques étudiées par Résonance Magnétique Nucléaire du Solide(2014), ANR-13-PDOC-0017,SUPRAMOL,Structures d'Assemblages Supramoléculaires par RMN du Solide : le Pseudopilus du Système de Sécrétion de Type II et le Tube de Queue du Bactériophage(2013), ANR-17-CE11-0035,SFAS,Structure et fonctions de motifs amyloïdes impliqués dans la transduction du signal(2017), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 648974,H2020,ERC-2014-CoG,P-MEM-NMR(2015), European Project: 639020,H2020,ERC-2014-STG,Weakinteract(2015), European Project: 661799,H2020,H2020-MSCA-IF-2014,COMPLEX-fastMAS-NMR(2016), European Project: 624918,EC:FP7:PEOPLE,FP7-PEOPLE-2013-IIF,MEM-MAS(2014), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), U.S. Department of Energy [Washington] (DOE)-UT-Battelle, LLC-Stony Brook University [SUNY] (SBU), and State University of New York (SUNY)-State University of New York (SUNY)
- Subjects
0301 basic medicine ,Protein Folding ,Amyloid ,Prions ,Prion strain ,Model system ,Amyloidogenic Proteins ,Computational biology ,Biology ,010402 general chemistry ,01 natural sciences ,Models, Biological ,Podospora anserina ,Fungal Proteins ,prion ,03 medical and health sciences ,Protein Aggregates ,0302 clinical medicine ,Podospora ,Amino Acid Sequence ,Prion protein ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Conserved Sequence ,030304 developmental biology ,cross-seeding ,0303 health sciences ,Multidisciplinary ,food and beverages ,amyloid ,Biological Sciences ,biology.organism_classification ,Sequence identity ,0104 chemical sciences ,Protein Structure, Tertiary ,[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,Strain specificity ,nuclear magnetic resonance ,030104 developmental biology ,sequence to fold ,Sequence Alignment ,030217 neurology & neurosurgery - Abstract
Neurodegenerative disorders are frequently associated with β-sheet-rich amyloid deposits. Amyloid-forming proteins can aggregate under different structural conformations known as strains, which can exhibit a prion-like behaviour and distinct patho-phenotypes. Precise molecular determinants defining strain specificity and cross-strain interactions (cross-seeding) are currently unknown. The HET-s prion protein from the fungus Podospora anserina represents a model system to study the fundamental properties of prion amyloids. Here, we report the amyloid prion structure of HELLF, a distant homolog of the model prion HET-s. We find that these two amyloids, sharing only 17% sequence identity, have nearly identical β-solenoid folds but lack cross-seeding ability in vivo, indicating that prion specificity can differ in extremely similar amyloid folds. We engineer the HELLF sequence to explore the limits of the sequence-to-fold conservation and to pinpoint determinants of cross-seeding and prion specificity. We find that amyloid fold conservation occurs even at an exceedingly low level of identity to HET-s (5%). Next, we derive a HELLF-based sequence, termed HEC, able to breach the cross-seeding barrier in vivo between HELLF and HET-s, unveiling determinants controlling cross-seeding at residue level. These findings show that virtually identical amyloid backbone structures might not be sufficient for cross-seeding and that critical side-chain positions could determine the seeding specificity of an amyloid fold. Our work redefines the conceptual boundaries of prion strain and shed new light on key molecular features concerning an important class of pathogenic agents.
- Published
- 2021
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