Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats
Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/72908 |
| _version_ | 1797998473403957248 |
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| author | Iga Kucharska Lamia Hossain Danton Ivanochko Qiren Yang John L Rubinstein Régis Pomès Jean-Philippe Julien |
| author_facet | Iga Kucharska Lamia Hossain Danton Ivanochko Qiren Yang John L Rubinstein Régis Pomès Jean-Philippe Julien |
| author_sort | Iga Kucharska |
| collection | DOAJ |
| description | Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines. |
| first_indexed | 2024-04-11T10:49:17Z |
| format | Article |
| id | doaj.art-d77aa415a45c4b3ea7da0686d84f0e1a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:17Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d77aa415a45c4b3ea7da0686d84f0e1a2022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.72908Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeatsIga Kucharska0https://orcid.org/0000-0001-6150-3419Lamia Hossain1Danton Ivanochko2Qiren Yang3John L Rubinstein4https://orcid.org/0000-0003-0566-2209Régis Pomès5https://orcid.org/0000-0003-3068-9833Jean-Philippe Julien6https://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, CanadaProgram 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, 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, CanadaMalaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.https://elifesciences.org/articles/72908P. vivaxcircumsporozoite proteinantibodiesstructural biology |
| spellingShingle | Iga Kucharska Lamia Hossain Danton Ivanochko Qiren Yang John L Rubinstein Régis Pomès Jean-Philippe Julien Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats eLife P. vivax circumsporozoite protein antibodies structural biology |
| title | Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| title_full | Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| title_fullStr | Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| title_full_unstemmed | Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| title_short | Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| title_sort | structural basis of plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats |
| topic | P. vivax circumsporozoite protein antibodies structural biology |
| url | https://elifesciences.org/articles/72908 |
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