Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.

Plasmodium parasites use specialized ligands which bind to red blood cell (RBC) receptors during invasion. Defining the mechanism of receptor recognition is essential for the design of interventions against malaria. Here, we present the structural basis for Duffy antigen (DARC) engagement by P. viva...

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Autores principales:	Joseph D Batchelor, Brian M Malpede, Natalie S Omattage, Gregory T DeKoster, Katherine A Henzler-Wildman, Niraj H Tolia
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ea763e2b0e364f1d9a86332cb6ebbbb2
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spelling	oai:doaj.org-article:ea763e2b0e364f1d9a86332cb6ebbbb22021-11-18T06:07:08ZRed blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.1553-73661553-737410.1371/journal.ppat.1003869https://doaj.org/article/ea763e2b0e364f1d9a86332cb6ebbbb22014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24415938/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Plasmodium parasites use specialized ligands which bind to red blood cell (RBC) receptors during invasion. Defining the mechanism of receptor recognition is essential for the design of interventions against malaria. Here, we present the structural basis for Duffy antigen (DARC) engagement by P. vivax Duffy binding protein (DBP). We used NMR to map the core region of the DARC ectodomain contacted by the receptor binding domain of DBP (DBP-RII) and solved two distinct crystal structures of DBP-RII bound to this core region of DARC. Isothermal titration calorimetry studies show these structures are part of a multi-step binding pathway, and individual point mutations of residues contacting DARC result in a complete loss of RBC binding by DBP-RII. Two DBP-RII molecules sandwich either one or two DARC ectodomains, creating distinct heterotrimeric and heterotetrameric architectures. The DARC N-terminus forms an amphipathic helix upon DBP-RII binding. The studies reveal a receptor binding pocket in DBP and critical contacts in DARC, reveal novel targets for intervention, and suggest that targeting the critical DARC binding sites will lead to potent disruption of RBC engagement as complex assembly is dependent on DARC binding. These results allow for models to examine inter-species infection barriers, Plasmodium immune evasion mechanisms, P. knowlesi receptor-ligand specificity, and mechanisms of naturally acquired P. vivax immunity. The step-wise binding model identifies a possible mechanism by which signaling pathways could be activated during invasion. It is anticipated that the structural basis of DBP host-cell engagement will enable development of rational therapeutics targeting this interaction.Joseph D BatchelorBrian M MalpedeNatalie S OmattageGregory T DeKosterKatherine A Henzler-WildmanNiraj H ToliaPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 1, p e1003869 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Joseph D Batchelor Brian M Malpede Natalie S Omattage Gregory T DeKoster Katherine A Henzler-Wildman Niraj H Tolia Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
description	Plasmodium parasites use specialized ligands which bind to red blood cell (RBC) receptors during invasion. Defining the mechanism of receptor recognition is essential for the design of interventions against malaria. Here, we present the structural basis for Duffy antigen (DARC) engagement by P. vivax Duffy binding protein (DBP). We used NMR to map the core region of the DARC ectodomain contacted by the receptor binding domain of DBP (DBP-RII) and solved two distinct crystal structures of DBP-RII bound to this core region of DARC. Isothermal titration calorimetry studies show these structures are part of a multi-step binding pathway, and individual point mutations of residues contacting DARC result in a complete loss of RBC binding by DBP-RII. Two DBP-RII molecules sandwich either one or two DARC ectodomains, creating distinct heterotrimeric and heterotetrameric architectures. The DARC N-terminus forms an amphipathic helix upon DBP-RII binding. The studies reveal a receptor binding pocket in DBP and critical contacts in DARC, reveal novel targets for intervention, and suggest that targeting the critical DARC binding sites will lead to potent disruption of RBC engagement as complex assembly is dependent on DARC binding. These results allow for models to examine inter-species infection barriers, Plasmodium immune evasion mechanisms, P. knowlesi receptor-ligand specificity, and mechanisms of naturally acquired P. vivax immunity. The step-wise binding model identifies a possible mechanism by which signaling pathways could be activated during invasion. It is anticipated that the structural basis of DBP host-cell engagement will enable development of rational therapeutics targeting this interaction.
format	article
author	Joseph D Batchelor Brian M Malpede Natalie S Omattage Gregory T DeKoster Katherine A Henzler-Wildman Niraj H Tolia
author_facet	Joseph D Batchelor Brian M Malpede Natalie S Omattage Gregory T DeKoster Katherine A Henzler-Wildman Niraj H Tolia
author_sort	Joseph D Batchelor
title	Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
title_short	Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
title_full	Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
title_fullStr	Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
title_full_unstemmed	Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.
title_sort	red blood cell invasion by plasmodium vivax: structural basis for dbp engagement of darc.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ea763e2b0e364f1d9a86332cb6ebbbb2
work_keys_str_mv	AT josephdbatchelor redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc AT brianmmalpede redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc AT nataliesomattage redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc AT gregorytdekoster redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc AT katherineahenzlerwildman redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc AT nirajhtolia redbloodcellinvasionbyplasmodiumvivaxstructuralbasisfordbpengagementofdarc
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Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC.

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