Epitopes described in "Structures of Abeta-related peptide--monoclonal antibody complexes."

Article Authors:Anna Gardberg; Lezlee Dice; Kathleen Pridgen; Jan Ko; Paul Patterson; Susan Ou; Ronald Wetzel; Chris Dealwis
Article Title:Structures of Abeta-related peptide--monoclonal antibody complexes.
Reference Detail
Reference ID:1014979
Abstract:Passive immunotherapy (PI) is being explored as a potential therapeutic against Alzheimer's disease. The most promising antibodies (Abs) used in PI target the EFRH motif of the Abeta N-terminus. The monoclonal anti-Abeta Ab PFA1 recognizes the EFRH epitope of Abeta. PFA1 has a high affinity for Abeta fibrils and protofibrils (0.1 nM), as well as good affinity for Abeta monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyroglutamate peptide pyro-Glu3-Abeta with a 77-fold loss in affinity compared to the WT Abeta(1-8). Furthermore, our earlier work illustrated PFA1's potential for cross-reactivity. The receptor tyrosine kinase Ror2, which plays a role in skeletal and bone formation, possesses the EFRH sequence. PFA1 Fab binds the Ror2(518-525) peptide sequence REEFRHEA with a 3-fold enhancement over WT Abeta(1-8). In this work, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-Abeta peptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 A, respectively. As with wild-type Abeta, these peptides bind to the Fab via a combination of charge- and shape-complementarity, hydrogen-bonding, and hydrophobic interactions. Comparison of the structures of the four peptides Abeta(1-8), Grip1, pyro-Glu3-Abeta(3-8), and Ror2 in complex with PFA1 shows that the greatest conformational flexibility occurs at residues 2 to 3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1 and its ability to recognize Abeta N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyroglutamate Abeta.
Affiliations:Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.
Reference Type:Literature
PubMed ID:19385664
Journal Volume:48
Article Pages:5210-7
Journal ISSN:0006-2960
Article Chemical List:Amyloid beta-Peptides;Antibodies, Monoclonal;Epitopes;Peptides
Article MeSH List:Amino Acid Sequence; Amyloid beta-Peptides(chemistry; immunology; metabolism); Antibodies, Monoclonal(chemistry; metabolism); Binding Sites; Crystallography, X-Ray; Epitopes(chemistry; metabolism); Hydrogen Bonding; Immunization, Passive; Models, Molecular; Molecular Sequence Data; Peptides(chemistry; metabolism); Protein Conformation
Curation Last Updated:2015-06-05 01:41:07