Dataset Information

Mechanisms of recognition of amyloid-? (A?) monomer, oligomer, and fibril by homologous antibodies.

ABSTRACT: 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.

SUBMITTER: Zhao J

PROVIDER: S-EPMC5672054 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies.

Zhao Jun J Nussinov Ruth R Ma Buyong B

The Journal of biological chemistry 20170918 44

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-β (Aβ) 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, t ...[more]

PMID: 28924036

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Project description:Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway.

Dataset Information

Mechanisms of recognition of amyloid-? (A?) monomer, oligomer, and fibril by homologous antibodies.

Publications

Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies.

Similar Datasets

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