title: Interprotofilament interactions between Alzheimer's Abeta1-42 peptides in amyloid fibrils revealed by cryoEM.
abstract: Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-beta (Abeta), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Abeta peptide (Abeta(1-42)), the most abundant Abeta peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human Abeta(1-42) peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to approximately 10-A resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for Abeta(17-42) fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature Abeta(1-42) fibrils is markedly different from previous cryoEM models of Abeta(1-40) fibrils. In our model, the C terminus of Abeta forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.
authors.affiliation: Graduate Program in Structural and Computational Biology and Molecular Biophysics, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hu
authors.forename: Htet
authors.initials: H
authors.lastname: Khant
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ludtke
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Schmid
authors.forename: Carl
authors.initials: C
authors.lastname: Frieden
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D020285:Cryoelectron Microscopy; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D010455:Peptides / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055672:Static Electricity
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42)