TY - JOUR
T1 - Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
AU - Ciudad, Sonia
AU - Puig, Eduard
AU - Botzanowski, Thomas
AU - Meigooni, Moeen
AU - Arango, Andres S.
AU - Do, Jimmy
AU - Mayzel, Maxim
AU - Bayoumi, Mariam
AU - Chaignepain, Stéphane
AU - Maglia, Giovanni
AU - Cianferani, Sarah
AU - Orekhov, Vladislav
AU - Tajkhorshid, Emad
AU - Bardiaux, Benjamin
AU - Carulla, Natàlia
N1 - Funding Information:
We acknowledge Montserrat Serra-Batiste, Martí Ninot-Pedrosa, Margarida Gairí and Jesús García for helpful discussions, sample preparation and NMR data acquisition at earlier stages of the project, James Tolchard for helpful discussions and building octamer models, Marta Vilaseca, Marina Gay, Carol V. Robinson and Michael Landreh for helpful discussions and MS data acquisition at earlier stages of the project, and Oscar Hernandez for help in calibration of CCS measurements. 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.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-16566-1
DO - 10.1038/s41467-020-16566-1
M3 - Article
C2 - 32541820
AN - SCOPUS:85086446943
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3014
ER -