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Title: Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11

Abstract

Plasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 – the leading malaria vaccine against P. falciparum (Pf) – has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [2]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [2]
  1. The Hospital for Sick Children Research Inst., Toronto, ON (Canada)
  2. The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1736286
Grant/Contract Number:  
AC02-06CH11357; SC0012704; ACB-12002; 1S10OD12289-01 A1; P41GM111244; KP1605010
Resource Type:
Accepted Manuscript
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 9; Journal Issue: 11, 2020; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kucharska, Iga, Thai, Elaine, Srivastava, Ananya, Rubinstein, John L., Pomès, Régis, and Julien, Jean-Philippe. Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11. United States: N. p., 2020. Web. https://doi.org/10.7554/elife.59018.
Kucharska, Iga, Thai, Elaine, Srivastava, Ananya, Rubinstein, John L., Pomès, Régis, & Julien, Jean-Philippe. Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11. United States. https://doi.org/10.7554/elife.59018
Kucharska, Iga, Thai, Elaine, Srivastava, Ananya, Rubinstein, John L., Pomès, Régis, and Julien, Jean-Philippe. Mon . "Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11". United States. https://doi.org/10.7554/elife.59018. https://www.osti.gov/servlets/purl/1736286.
@article{osti_1736286,
title = {Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11},
author = {Kucharska, Iga and Thai, Elaine and Srivastava, Ananya and Rubinstein, John L. and Pomès, Régis and Julien, Jean-Philippe},
abstractNote = {Plasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 – the leading malaria vaccine against P. falciparum (Pf) – has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.},
doi = {10.7554/elife.59018},
journal = {eLife},
number = 11, 2020,
volume = 9,
place = {United States},
year = {2020},
month = {11}
}

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