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Structure. 2018 Dec 4;26(12):1626-1634.e4. doi: 10.1016/j.str.2018.08.012. Epub 2018 Oct 11.

Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
4
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
5
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN Leiden, the Netherlands.
6
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN Leiden, the Netherlands; Department of Neurology, Amsterdam Neuroscience, Academic Medical Center, Meidreefberg 9, 1105 AZ Amsterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
7
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wilson@scripps.edu.

Abstract

Aggregation of the hyperphosphorylated protein tau into neurofibrillary tangles and neuropil threads is a hallmark of Alzheimer disease (AD). Identification and characterization of the epitopes recognized by anti-tau antibodies might shed light on the molecular mechanisms of AD pathogenesis. Here we report on the biochemical and structural characterization of a tau-specific monoclonal antibody CBTAU-24.1, which was isolated from the human memory B cell repertoire. Immunohistochemical staining with CBTAU-24.1 specifically detects pathological tau structures in AD brain samples. The crystal structure of CBTAU-24.1 Fab with a phosphorylated tau peptide revealed recognition of a unique epitope (Ser235-Leu243) in the tau proline-rich domain. Interestingly, the antibody can bind tau regardless of phosphorylation state of its epitope region and also recognizes both monomeric and paired helical filament tau irrespective of phosphorylation status. This human anti-tau antibody and its unique epitope may aid in development of diagnostics and/or therapeutic AD strategies.

KEYWORDS:

Alzheimer disease; diagnostics; hyperphosphorylation; monoclonal antibody; tau; therapeutics; x-ray crystallography

PMID:
30318466
DOI:
10.1016/j.str.2018.08.012

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