6rhy
Structure of pore-forming amyloid-beta tetramers
Structural highlights
Publication Abstract from PubMedFormation of amyloid-beta (Abeta) 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 Abeta oligomer formed in a membrane mimicking environment, namely an Abeta(1-42) tetramer, which comprises a six stranded beta-sheet core. The two faces of the beta-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed. By increasing the concentration of Abeta(1-42) in the sample, Abeta(1-42) octamers are also formed, made by two Abeta(1-42) tetramers facing each other forming a beta-sandwich structure. Notably, Abeta(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 beta-sheets edges of the oligomers. Abeta(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage.,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 Nat Commun. 2020 Jun 15;11(1):3014. doi: 10.1038/s41467-020-16566-1. PMID:32541820[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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