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

Heng Zhang, Xueyong Zhu, Gabriel Pascual, Jehangir S. Wadia, Elissa Keogh, Jeroen J. Hoozemans, Berdien Siregar, Hanna Inganäs, Esther J. M. Stoop, Jaap Goudsmit, Adrian Apetri, Wouter Koudstaal, Ian A. Wilson

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1626-1634.e4
JournalStructure
Volume26
Issue number12
Early online date12 Sep 2018
DOIs
Publication statusPublished - 2018

Cite this

Zhang, H., Zhu, X., Pascual, G., Wadia, J. S., Keogh, E., Hoozemans, J. J., ... Wilson, I. A. (2018). Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody. Structure, 26(12), 1626-1634.e4. https://doi.org/10.1016/j.str.2018.08.012
Zhang, Heng ; Zhu, Xueyong ; Pascual, Gabriel ; Wadia, Jehangir S. ; Keogh, Elissa ; Hoozemans, Jeroen J. ; Siregar, Berdien ; Inganäs, Hanna ; Stoop, Esther J. M. ; Goudsmit, Jaap ; Apetri, Adrian ; Koudstaal, Wouter ; Wilson, Ian A. / Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody. In: Structure. 2018 ; Vol. 26, No. 12. pp. 1626-1634.e4.
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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.",
author = "Heng Zhang and Xueyong Zhu and Gabriel Pascual and Wadia, {Jehangir S.} and Elissa Keogh and Hoozemans, {Jeroen J.} and Berdien Siregar and Hanna Ingan{\"a}s and Stoop, {Esther J. M.} and Jaap Goudsmit and Adrian Apetri and Wouter Koudstaal and Wilson, {Ian A.}",
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year = "2018",
doi = "10.1016/j.str.2018.08.012",
language = "English",
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Zhang, H, Zhu, X, Pascual, G, Wadia, JS, Keogh, E, Hoozemans, JJ, Siregar, B, Inganäs, H, Stoop, EJM, Goudsmit, J, Apetri, A, Koudstaal, W & Wilson, IA 2018, 'Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody' Structure, vol. 26, no. 12, pp. 1626-1634.e4. https://doi.org/10.1016/j.str.2018.08.012

Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody. / Zhang, Heng; Zhu, Xueyong; Pascual, Gabriel; Wadia, Jehangir S.; Keogh, Elissa; Hoozemans, Jeroen J.; Siregar, Berdien; Inganäs, Hanna; Stoop, Esther J. M.; Goudsmit, Jaap; Apetri, Adrian; Koudstaal, Wouter; Wilson, Ian A.

In: Structure, Vol. 26, No. 12, 2018, p. 1626-1634.e4.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody

AU - Zhang, Heng

AU - Zhu, Xueyong

AU - Pascual, Gabriel

AU - Wadia, Jehangir S.

AU - Keogh, Elissa

AU - Hoozemans, Jeroen J.

AU - Siregar, Berdien

AU - Inganäs, Hanna

AU - Stoop, Esther J. M.

AU - Goudsmit, Jaap

AU - Apetri, Adrian

AU - Koudstaal, Wouter

AU - Wilson, Ian A.

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

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DO - 10.1016/j.str.2018.08.012

M3 - Article

VL - 26

SP - 1626-1634.e4

JO - Structure

JF - Structure

SN - 0969-2126

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ER -