The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site

ABSTRACT Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface...

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Autores principales:	Ivan Campeotto, Francis Galaway, Shahid Mehmood, Lea K. Barfod, Doris Quinkert, Vinayaka Kotraiah, Timothy W. Phares, Katherine E. Wright, Ambrosius P. Snijders, Simon J. Draper, Matthew K. Higgins, Gavin J. Wright
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Plasmodium falciparum crystal structure malaria monoclonal antibodies protein-protein interactions vaccines Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8d221c225ab1482e998827f18ac8ad0f
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spelling	oai:doaj.org-article:8d221c225ab1482e998827f18ac8ad0f2021-11-15T16:19:07ZThe Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site10.1128/mBio.01566-202150-7511https://doaj.org/article/8d221c225ab1482e998827f18ac8ad0f2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01566-20https://doaj.org/toc/2150-7511ABSTRACT Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA, and RIPR can inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or noninhibitory for RH5 binding. Using a Fab fragment as a crystallization chaperone, we determined the crystal structure of the RH5 binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in guiding the development of blood-stage malaria vaccines that target RH5. IMPORTANCE Malaria is a deadly infectious disease primarily caused by the parasite Plasmodium falciparum. It remains a major global health problem, and there is no highly effective vaccine. A parasite protein called RH5 is centrally involved in the invasion of host red blood cells, making it—and the other parasite proteins it interacts with—promising vaccine targets. We recently identified a protein called P113 that binds RH5, suggesting that it anchors RH5 to the parasite surface. In this paper, we use structural biology to locate and characterize the RH5 binding region on P113. These findings will be important to guide the development of new antimalarial vaccines to ultimately prevent this disease, which affects some of the poorest people on the planet.Ivan CampeottoFrancis GalawayShahid MehmoodLea K. BarfodDoris QuinkertVinayaka KotraiahTimothy W. PharesKatherine E. WrightAmbrosius P. SnijdersSimon J. DraperMatthew K. HigginsGavin J. WrightAmerican Society for MicrobiologyarticlePlasmodium falciparumcrystal structuremalariamonoclonal antibodiesprotein-protein interactionsvaccinesMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium falciparum crystal structure malaria monoclonal antibodies protein-protein interactions vaccines Microbiology QR1-502
spellingShingle	Plasmodium falciparum crystal structure malaria monoclonal antibodies protein-protein interactions vaccines Microbiology QR1-502 Ivan Campeotto Francis Galaway Shahid Mehmood Lea K. Barfod Doris Quinkert Vinayaka Kotraiah Timothy W. Phares Katherine E. Wright Ambrosius P. Snijders Simon J. Draper Matthew K. Higgins Gavin J. Wright The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
description	ABSTRACT Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA, and RIPR can inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or noninhibitory for RH5 binding. Using a Fab fragment as a crystallization chaperone, we determined the crystal structure of the RH5 binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in guiding the development of blood-stage malaria vaccines that target RH5. IMPORTANCE Malaria is a deadly infectious disease primarily caused by the parasite Plasmodium falciparum. It remains a major global health problem, and there is no highly effective vaccine. A parasite protein called RH5 is centrally involved in the invasion of host red blood cells, making it—and the other parasite proteins it interacts with—promising vaccine targets. We recently identified a protein called P113 that binds RH5, suggesting that it anchors RH5 to the parasite surface. In this paper, we use structural biology to locate and characterize the RH5 binding region on P113. These findings will be important to guide the development of new antimalarial vaccines to ultimately prevent this disease, which affects some of the poorest people on the planet.
format	article
author	Ivan Campeotto Francis Galaway Shahid Mehmood Lea K. Barfod Doris Quinkert Vinayaka Kotraiah Timothy W. Phares Katherine E. Wright Ambrosius P. Snijders Simon J. Draper Matthew K. Higgins Gavin J. Wright
author_facet	Ivan Campeotto Francis Galaway Shahid Mehmood Lea K. Barfod Doris Quinkert Vinayaka Kotraiah Timothy W. Phares Katherine E. Wright Ambrosius P. Snijders Simon J. Draper Matthew K. Higgins Gavin J. Wright
author_sort	Ivan Campeotto
title	The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
title_short	The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
title_full	The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
title_fullStr	The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
title_full_unstemmed	The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site
title_sort	structure of the cysteine-rich domain of <named-content content-type="genus-species">plasmodium falciparum</named-content> p113 identifies the location of the rh5 binding site
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8d221c225ab1482e998827f18ac8ad0f
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The Structure of the Cysteine-Rich Domain of <named-content content-type="genus-species">Plasmodium falciparum</named-content> P113 Identifies the Location of the RH5 Binding Site

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