Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11
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) – ha...
| Main Authors: | , , , , , |
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| Format: | Article |
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eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/59018 |
| _version_ | 1811201436556460032 |
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| author | Iga Kucharska Elaine Thai Ananya Srivastava John L Rubinstein Régis Pomès Jean-Philippe Julien |
| author_facet | Iga Kucharska Elaine Thai Ananya Srivastava John L Rubinstein Régis Pomès Jean-Philippe Julien |
| author_sort | Iga Kucharska |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:21:42Z |
| format | Article |
| id | doaj.art-e9f37c736a9f4e2ba78a3da2bcc96791 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:21:42Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e9f37c736a9f4e2ba78a3da2bcc967912022-12-22T03:52:07ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.59018Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11Iga Kucharska0https://orcid.org/0000-0001-6150-3419Elaine Thai1https://orcid.org/0000-0001-7576-154XAnanya Srivastava2John L Rubinstein3https://orcid.org/0000-0003-0566-2209Régis Pomès4https://orcid.org/0000-0003-3068-9833Jean-Philippe Julien5https://orcid.org/0000-0001-7602-3995Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, CanadaProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, CanadaProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, CanadaPlasmodium 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.https://elifesciences.org/articles/59018antibodyPlasmodium bergheimolecular biologyCircumsporozoite proteinstructural biology |
| spellingShingle | Iga Kucharska Elaine Thai Ananya Srivastava John L Rubinstein Régis Pomès Jean-Philippe Julien Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 eLife antibody Plasmodium berghei molecular biology Circumsporozoite protein structural biology |
| title | Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 |
| title_full | Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 |
| title_fullStr | Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 |
| title_full_unstemmed | Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 |
| title_short | Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11 |
| title_sort | structural ordering of the plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3d11 |
| topic | antibody Plasmodium berghei molecular biology Circumsporozoite protein structural biology |
| url | https://elifesciences.org/articles/59018 |
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