Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 44, Pages 18325-18343Publisher
ELSEVIER
DOI: 10.1074/jbc.M117.801514
Keywords
Alzheimer disease; amyloid; amyloid-beta (AB); antibody; immunotherapy; protein dynamic
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Funding
- NCI, National Institutes of Health [HHSN261200800001E]
- NCI, National Institutes of Health, Center for Cancer Research
- NIDCD, National Institutes of Health
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Alzheimer's disease is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapy is a promising approach, but amyloid antibody structural information is limited. Here we simulate the recognition of monomeric, oligomeric, and fibril amyloid- (A) by three homologous antibodies (solanezumab, crenezumab, and their chimera, CreneFab). Solanezumab only binds the monomer, whereas crenezumab and CreneFab can recognize different oligomerization states; however, the structural basis for this observation is not understood. We successfully identified stable complexes of crenezumab with A pentamer (oligomer model) and 16-mer (fibril model). It is noteworthy that solanezumab targets A residues 16-26 preferentially in the monomeric state; conversely, crenezumab consistently targets residues 13-16 in different oligomeric states. Unlike the buried monomeric peptide in solanezumab's complementarity-determining region, crenezumab binds the oligomer's lateral and edge residues. Surprisingly, crenezumab's complementarity-determining region loops can effectively bind the A fibril lateral surface around the same 13-16 region. The constant domain influences antigen recognition through entropy redistribution. Different constant domain residues in solanezumab/crenezumab/chimera influence the binding of A aggregates. Collectively, we provide molecular insight into the recognition mechanisms facilitating antibody design.
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