Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1
Apical Membrane Antigen 1 (AMA1) plays a vital role in the invasion of the host erythrocyte by the malaria parasite, Plasmodium. It is thus an important target for vaccine and anti-malaria therapeutic strategies that block the invasion process. AMA1, present on the surface of the parasite, interacts...
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Elsevier
2024-12-01
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| Series: | Journal of Structural Biology: X |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590152424000151 |
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| author | Frederick A. Saul Brigitte Vulliez-Le Normand Alexander Boes Holger Spiegel Clemens H.M. Kocken Bart W. Faber Graham A. Bentley |
| author_facet | Frederick A. Saul Brigitte Vulliez-Le Normand Alexander Boes Holger Spiegel Clemens H.M. Kocken Bart W. Faber Graham A. Bentley |
| author_sort | Frederick A. Saul |
| collection | DOAJ |
| description | Apical Membrane Antigen 1 (AMA1) plays a vital role in the invasion of the host erythrocyte by the malaria parasite, Plasmodium. It is thus an important target for vaccine and anti-malaria therapeutic strategies that block the invasion process. AMA1, present on the surface of the parasite, interacts with RON2, a component of the parasite’s rhoptry neck (RON) protein complex, which is transferred to the erythrocyte membrane during invasion. The D2 loop of AMA1 plays an essential role in invasion as it partially covers the RON2-binding site and must therefore be displaced for invasion to proceed. Several structural studies have shown that the D2 loop is very mobile, a property that is probably important for the function of AMA1. Here we present three crystal structures of AMA1 from P. falciparum (strains 3D7 and FVO) and P. vivax (strain Sal1), in which the D2 loop could be largely traced in the electron density maps. The D2 loop of PfAMA1-FVO and PvAMA1 (as a complex with a monoclonal antibody Fab) has a conformation previously noted in the P. knowlesi AMA1 structure. The D2 loop of PfAMA1-3D7, however, reveals a novel conformation. We analyse the conformational variability of the D2 loop in these structures, together with those previously reported. Three different conformations can be distinguished, all of which are highly helical and show some similarity in their secondary structure organisation. We discuss the significance of these observations in the light of the flexible nature of the D2 loop and its role in AMA1 function. |
| format | Article |
| id | doaj-art-e07f3fe089b443709f003b70b7311b82 |
| institution | DOAJ |
| issn | 2590-1524 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Structural Biology: X |
| spelling | doaj-art-e07f3fe089b443709f003b70b7311b822025-08-20T02:39:27ZengElsevierJournal of Structural Biology: X2590-15242024-12-011010011010.1016/j.yjsbx.2024.100110Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1Frederick A. Saul0Brigitte Vulliez-Le Normand1Alexander Boes2Holger Spiegel3Clemens H.M. Kocken4Bart W. Faber5Graham A. Bentley6Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Plate-forme de Cristallographie C2RT, 75015 Paris, France; Current address: Institut Pasteur, Université Paris Cité, 75015 Paris, FranceInstitut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, FranceFraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany; Current address: Leibniz-Institute for Interactive Materials, Aachen, GermanyFraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, GermanyDepartment of Parasitology, Biomedical Primate Research Centre, Rijswijk, the NetherlandsDepartment of Parasitology, Biomedical Primate Research Centre, Rijswijk, the Netherlands; Corresponding authors.Institut Pasteur, CNRS URA 2185, Unité d’Immunologie Structurale, 75015 Paris, France; Current address: Institut Pasteur, Université Paris Cité, 75015 Paris, France; Corresponding authors.Apical Membrane Antigen 1 (AMA1) plays a vital role in the invasion of the host erythrocyte by the malaria parasite, Plasmodium. It is thus an important target for vaccine and anti-malaria therapeutic strategies that block the invasion process. AMA1, present on the surface of the parasite, interacts with RON2, a component of the parasite’s rhoptry neck (RON) protein complex, which is transferred to the erythrocyte membrane during invasion. The D2 loop of AMA1 plays an essential role in invasion as it partially covers the RON2-binding site and must therefore be displaced for invasion to proceed. Several structural studies have shown that the D2 loop is very mobile, a property that is probably important for the function of AMA1. Here we present three crystal structures of AMA1 from P. falciparum (strains 3D7 and FVO) and P. vivax (strain Sal1), in which the D2 loop could be largely traced in the electron density maps. The D2 loop of PfAMA1-FVO and PvAMA1 (as a complex with a monoclonal antibody Fab) has a conformation previously noted in the P. knowlesi AMA1 structure. The D2 loop of PfAMA1-3D7, however, reveals a novel conformation. We analyse the conformational variability of the D2 loop in these structures, together with those previously reported. Three different conformations can be distinguished, all of which are highly helical and show some similarity in their secondary structure organisation. We discuss the significance of these observations in the light of the flexible nature of the D2 loop and its role in AMA1 function.http://www.sciencedirect.com/science/article/pii/S2590152424000151Apical Membrane Antigen 1Domain 2 loopVariable conformationPlasmodium antigenMalaria vaccine candidate |
| spellingShingle | Frederick A. Saul Brigitte Vulliez-Le Normand Alexander Boes Holger Spiegel Clemens H.M. Kocken Bart W. Faber Graham A. Bentley Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 Journal of Structural Biology: X Apical Membrane Antigen 1 Domain 2 loop Variable conformation Plasmodium antigen Malaria vaccine candidate |
| title | Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 |
| title_full | Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 |
| title_fullStr | Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 |
| title_full_unstemmed | Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 |
| title_short | Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1 |
| title_sort | conformational variability in the d2 loop of plasmodium apical membrane antigen 1 |
| topic | Apical Membrane Antigen 1 Domain 2 loop Variable conformation Plasmodium antigen Malaria vaccine candidate |
| url | http://www.sciencedirect.com/science/article/pii/S2590152424000151 |
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