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

Iga Kucharska, Elaine Thai, Ananya Srivastava, View ORCID ProfileJohn Rubinstein, View ORCID ProfileRégis Pomès, View ORCID ProfileJean-Philippe Julien
doi: https://doi.org/10.1101/2020.06.02.131110
Iga Kucharska
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
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Elaine Thai
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
2Department of Biochemistry, University of Toronto, ON M5G 0A4, Canada
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Ananya Srivastava
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
2Department of Biochemistry, University of Toronto, ON M5G 0A4, Canada
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John Rubinstein
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
2Department of Biochemistry, University of Toronto, ON M5G 0A4, Canada
3Department of Medical Biophysics, University of Toronto, ON M5G 1L7, Canada
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Régis Pomès
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
2Department of Biochemistry, University of Toronto, ON M5G 0A4, Canada
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Jean-Philippe Julien
1Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
2Department of Biochemistry, University of Toronto, ON M5G 0A4, Canada
4Department of Immunology, University of Toronto, ON M5G 0A4, Canada
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  • For correspondence: jean-philippe.julien@sickkids.ca
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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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 04, 2020.
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Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11
Iga Kucharska, Elaine Thai, Ananya Srivastava, John Rubinstein, Régis Pomès, Jean-Philippe Julien
bioRxiv 2020.06.02.131110; doi: https://doi.org/10.1101/2020.06.02.131110
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Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11
Iga Kucharska, Elaine Thai, Ananya Srivastava, John Rubinstein, Régis Pomès, Jean-Philippe Julien
bioRxiv 2020.06.02.131110; doi: https://doi.org/10.1101/2020.06.02.131110

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