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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.
AuthorsStéphane Gangnard, Anita Lewit-Bentley, Sébastien Dechavanne, Anand Srivastava, Faroudja Amirat, Graham A Bentley, Benoît Gamain
JournalScientific reports (Sci Rep) Vol. 5 Pg. 14868 (Oct 09 2015) ISSN: 2045-2322 [Electronic] England
PMID26450557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Immune Sera
  • Malaria Vaccines
  • VAR2CSA protein, Plasmodium falciparum
  • Chondroitin Sulfates
Topics
  • Amino Acid Sequence
  • Animals
  • Antibodies, Protozoan (blood, immunology)
  • Antigens, Protozoan (chemistry, genetics, immunology)
  • Binding Sites (genetics, immunology)
  • Chondroitin Sulfates (immunology, metabolism)
  • Crystallography, X-Ray
  • Erythrocytes (immunology, parasitology)
  • Female
  • Host-Parasite Interactions (immunology)
  • Humans
  • Immune Sera (immunology)
  • Malaria Vaccines (administration & dosage, immunology)
  • Malaria, Falciparum (immunology, parasitology, prevention & control)
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Placenta (immunology, metabolism, parasitology)
  • Plasmodium falciparum (immunology, metabolism, physiology)
  • Pregnancy
  • Protein Binding (immunology)
  • Protein Structure, Tertiary
  • Rabbits
  • Sequence Homology, Amino Acid

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