title: Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A.
abstract: Plasmodium falciparum-infected erythrocytes bind to chondroitin sulfate A (CSA) in the placenta via the VAR2CSA protein, a member of the P. falciparum erythrocyte membrane protein-1 family, leading to life-threatening malaria in pregnant women with severe effects on their fetuses and newborns. Here we describe the structure of the CSA binding DBL3x domain, a Duffy binding-like (DBL) domain of VAR2CSA. By forming a complex of DBL3x with CSA oligosaccharides and determining its structure, we have identified the CSA binding site to be a cluster of conserved positively charged residues on subdomain 2 and subdomain 3. Mutation or chemical modification of lysine residues at the site markedly diminished CSA binding to DBL3x. The location of the CSA binding site is an important step forward in the molecular understanding of pregnancy-associated malaria and offers a new target for vaccine development.
authors.affiliation: Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, Maryland 20852, USA. ksingh@niaid.nih.gov
authors.forename: Kavita
authors.initials: K
authors.lastname: Singh
authors.forename: Apostolos G
authors.initials: AG
authors.lastname: Gittis
authors.forename: Phuc
authors.initials: P
authors.lastname: Nguyen
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
authors.forename: David N
authors.initials: DN
authors.lastname: Garboczi
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002809:Chondroitin Sulfates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000737:chemistry / Q000469:parasitology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D046911:Macromolecular Substances / Q000737:chemistry; D016778:Malaria, Falciparum / Q000150:complications / Q000469:parasitology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010920:Placenta / Q000469:parasitology; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000235:genetics / Q000472:pathogenicity; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000469:parasitology; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity
chemical_list: D000953:Antigens, Protozoan; D046911:Macromolecular Substances; D015800:Protozoan Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; D002809:Chondroitin Sulfates