Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.
Alzheimer's disease (AD) is the most common form of dementia. Amyloid-beta (A beta) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on A beta, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-A beta antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the A beta peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the A beta peptide. The structures reveal the molecular basis for WO2 recognition and binding of A beta. The A beta peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound A beta peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of A beta, such as WO2, hold promise for therapeutic development.
Miles
Luke A
LA
Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
Wun
Kwok S
KS
Crespi
Gabriela A N
GA
Fodero-Tavoletti
Michelle T
MT
Galatis
Denise
D
Bagley
Christopher J
CJ
Beyreuther
Konrad
K
Masters
Colin L
CL
Cappai
Roberto
R
McKinstry
William J
WJ
Barnham
Kevin J
KJ
Parker
Michael W
MW
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry; D018360:Crystallography, X-Ray; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry* / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D008670:Metals; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012984:Software; D013499:Surface Properties; D013696:Temperature
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D016056:Immunodominant Epitopes; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D008670:Metals