title: Structure of the DBL3X-DBL4ε region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions.
abstract: The human malaria parasite, Plasmodium falciparum, is able to evade spleen-mediated clearing from blood stream by sequestering in peripheral organs. This is due to the adhesive properties conferred by the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family exported by the parasite to the surface of infected erythrocytes. Expression of the VAR2CSA variant of PfEMP1 leads to pregnancy-associated malaria, which occurs when infected erythrocytes massively sequester in the placenta by binding to low-sulfated Chondroitin Sulfate A (CSA) present in the intervillous spaces. VAR2CSA is a 350 kDa protein that carries six Duffy-Binding Like (DBL) domains, one Cysteine-rich Inter-Domain Regions (CIDR) and several inter-domain regions. In the present paper, we report for the first time the crystal structure at 2.9 Å of a VAR2CSA double domain, DBL3X-DBL4ε, from the FCR3 strain. DBL3X and DBL4ε share a large contact interface formed by residues that are invariant or highly conserved in VAR2CSA variants, which suggests that these two central DBL domains (DBL3X-DBL4ε) contribute significantly to the structuring of the functional VAR2CSA extracellular region. We have also examined the antigenicity of peptides corresponding to exposed loop regions of the DBL4ε structure.
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134 Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of excellence GR-Ex, Paris, France.|Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.|Centre National de la Recherche Scientifique URA2185, 25 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gangnard
authors.affiliation: Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.|Centre National de la Recherche Scientifique URA2185, 25 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Lewit-Bentley
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134 Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of excellence GR-Ex, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dechavanne
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134 Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of excellence GR-Ex, Paris, France.
authors.forename: Anand
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.|Centre National de la Recherche Scientifique URA2185, 25 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Faroudja
authors.initials: F
authors.lastname: Amirat
authors.affiliation: Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.|Centre National de la Recherche Scientifique URA2185, 25 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Bentley
authors.affiliation: Inserm UMR_1134, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134 Paris, France.|Institut National de la Transfusion Sanguine, Paris, France.|Laboratory of excellence GR-Ex, Paris, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Gamain
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002809:Chondroitin Sulfates / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010920:Placenta / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011817:Rabbits; D017386:Sequence Homology, Amino Acid
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007106:Immune Sera; D017780:Malaria Vaccines; C512601:VAR2CSA protein, Plasmodium falciparum; D002809:Chondroitin Sulfates