Format

Send to

Choose Destination
J Biol Chem. 2017 Nov 3;292(44):18325-18343. doi: 10.1074/jbc.M117.801514. Epub 2017 Sep 18.

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

Author information

1
From the Cancer and Inflammation Program, NCI-Frederick, Frederick, Maryland 21702.
2
the Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCI-Frederick, Frederick, Maryland 21702, and.
3
the Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
4
the Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCI-Frederick, Frederick, Maryland 21702, and mabuyong@mail.nih.gov.

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-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, the structural basis for this observation is not understood. We successfully identified stable complexes of crenezumab with Aβ pentamer (oligomer model) and 16-mer (fibril model). It is noteworthy that solanezumab targets Aβ 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 Aβ 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 Aβ aggregates. Collectively, we provide molecular insight into the recognition mechanisms facilitating antibody design.

KEYWORDS:

Alzheimer disease; amyloid; amyloid-beta (AB); antibody; immunotherapy; protein dynamic

PMID:
28924036
PMCID:
PMC5672054
DOI:
10.1074/jbc.M117.801514
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center