Epitopes described in "Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment."

Article Authors:Isabel Morgado; Karin Wieligmann; Magdalena Bereza; Raik Rönicke; Katrin Meinhardt; Karthikeyan Annamalai; Monika Baumann; Jessica Wacker; Peter Hortschansky; Miroslav Malešević; Christoph Parthier; Christian Mawrin; Cordelia Schiene-Fischer; Klaus G Reymann; Milton T Stubbs; Jochen Balbach; Matthias Görlach; Uwe Horn; Marcus Fändrich
Article Title:Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment.
Reference Detail
Reference ID:1025191
Abstract:Oligomers are intermediates of the -amyloid (A) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other A conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of A oligomers, such as those formed by A (1-40) and A (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes A residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with A assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature A fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of A conformers.
Affiliations:Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle, Saale, Germany.
Reference Type:Literature
PubMed ID:22814377
Journal:Proc Natl Acad Sci U S A
Journal Volume:109
Article Pages:12503-8
Journal ISSN:0027-8424
Article Chemical List:gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@57f01139;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@51fae249;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@2e1e50ab;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@48422234
Article MeSH List:Amino Acid Motifs; Amyloid beta-Peptides(chemistry); Antibodies, Monoclonal; Crystallography, X-Ray; Humans; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments(chemistry); Protein Multimerization; Protein Structure, Quaternary
Curation Last Updated:2015-01-18 20:19:37