title: Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease.
abstract: Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-β (Aβ) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar Aβ oligomers may be the major drivers of Aβ-mediated synaptic dysfunction. Structural information on these Aβ species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18-41 of the Aβ peptide (equivalent to the p3 α/γ-secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated Aβ dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar Aβ oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in Aβ folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease.
authors.affiliation: Commonwealth Scientific and Industrial Research Organization, Parkville, Victoria 3052, Australia. victor.streltsov@csiro.au
authors.forename: Victor A
authors.initials: VA
authors.lastname: Streltsov
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Varghese
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Nuttall
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D018360:Crystallography, X-Ray; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics; D012754:Sharks
chemical_list: D016229:Amyloid beta-Peptides; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases