Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
Autor: | Emad Tajkhorshid, Eduard Puig, Sonia Ciudad, Thomas Botzanowski, Mariam Bayoumi, Vladislav Yu. Orekhov, Benjamin Bardiaux, Giovanni Maglia, Sarah Cianférani, Andres S. Arango, Stéphane Chaignepain, Jimmy Do, Moeen Meigooni, Natàlia Carulla, Maxim Mayzel |
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Přispěvatelé: | Chemical Biology 1, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), 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), Institute for Research in Biomedicine [Barcelona, Spain] (IRB), University of Barcelona-Barcelona Institute of Science and Technology (BIST), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, University of Gothenburg (GU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Groningen [Groningen], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institute for Research in Biomedicine (IRB Barcelona) (IRB), Institute for Research in Biomedicine, This study was supported by MINECO (SAF2015-68789), the Fondation Recherche Médicale (AJE20151234751) and the Counseil Régional d’Aquitaine Limousin Poitou-Charentes (1R30117-00007559) to N.C. The authors G.M and N.C. acknowledge funds from Fundació La Marató de TV3 (20140730). B.B research was supported by the INCEPTION project (ANR-16-CONV-0005). E.T. was supported by the National Institutes of Health (P41-GM104601 and R01-GM123455) and also acknowledges computing resources provided by Blue Waters at National Center for Supercomputing Applications, and Extreme Science and Engineering Discovery Environment XSEDE (grant MCA06N060). V.O. research was supported by the Swedish Research Council Formas (2015-04614). S. Cianferani research was supported by Agence Nationale de la Recherche and the French Proteomic Infrastructure (ANR-10-INBS-08-03). N.C., S. Cianferani, T.B. and E.P. acknowledge the support of COST Action (BM1403). E.P. was a PhD fellow funded by MINECO (FPI). T.B. was a PhD fellow funded by Institut de Recherche Servier., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), 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), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
AMYLOID-BETA-PEPTIDE PROTEINS Science General Physics and Astronomy COLLISION CROSS-SECTIONS Conductivity Oligomer General Biochemistry Genetics and Molecular Biology Article ATOMIC-RESOLUTION STRUCTURE 03 medical and health sciences Molecular dynamics chemistry.chemical_compound CONFORMATIONS 0302 clinical medicine Tetramer Alzheimer Disease Humans Histone octamer Lipid bilayer lcsh:Science A-BETA Multidisciplinary Amyloid beta-Peptides CHANNELS PURIFICATION [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Brain Membrane structure and assembly General Chemistry Permeation Peptide Fragments NMR [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biophysics ALZHEIMERS-DISEASE 030104 developmental biology Membrane chemistry Biophysics lcsh:Q Solution-state NMR 030217 neurology & neurosurgery |
Zdroj: | Nature Communications, 11(1):3014. Nature Publishing Group Nature Communications Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.3014. ⟨10.1038/s41467-020-16566-1⟩ Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications, 2020, 11 (1), pp.3014. ⟨10.1038/s41467-020-16566-1⟩ |
ISSN: | 2041-1723 |
Popis: | Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimerʼs disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Aβ(1-42) in the sample, Aβ(1-42) octamers are also formed, made by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, Aβ(1-42) tetramers and octamers inserted into lipid bilayers as well-defined pores. To establish oligomer structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed a mechanism of membrane disruption in which water permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the oligomers. Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer´s disease. Here authors present the 3D- structure of an Aβ oligomer formed in a membrane mimicking environment and observe that Aβ tetramers and octamers inserted into lipid bilayers as well-defined pores. |
Databáze: | OpenAIRE |
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