Article abstract
Nature Structural & Molecular Biology 15, 932 - 938 (2008)
Published online: 24 August 2008 | doi:10.1038/nsmb.1479
Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A
Kavita Singh1, Apostolos G Gittis1, Phuc Nguyen1, D Channe Gowda2, Louis H Miller3 & David N Garboczi1
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.
- Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, Maryland 20852, USA.
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, H171, Hershey, Pennsylvania 17033, USA.
- Malaria Vaccine Development Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Rockville, Maryland 20852, USA.
Correspondence to: Kavita Singh1 e-mail: ksingh@niaid.nih.gov
Correspondence to: David N Garboczi1 e-mail: dgarboczi@niaid.nih.gov
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