Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage.
Fiche publication
Date publication
juin 2020
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah
Tous les auteurs :
Ciudad S, Puig E, Botzanowski T, Meigooni M, Arango AS, Do J, Mayzel M, Bayoumi M, Chaignepain S, Maglia G, Cianferani S, Orekhov V, Tajkhorshid E, Bardiaux B, Carulla N
Lien Pubmed
Résumé
Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer's 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.
Référence
Nat Commun. 2020 Jun 15;11(1):3014