Cited by 99Malaria Research and ControlBiochemical and Structural CharacterizationBlood groups and transfusion

Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A

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Singh, Kavita, Gittis, Apostolos G, Nguyen, Phuc, Gowda, D Channe, Miller, Louis H, Garboczi, David N·2008·Nature Structural & Molecular Biology

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.

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Authors
Singh, K., Gittis, A. G., Nguyen, P., Gowda, D. C., Miller, L. H., & Garboczi, D. N.
Affiliations
  • National Institutes of Health (US)
  • Pennsylvania State University (US)
Corresponding author
  • Singh, Kavita
  • Garboczi, David N
Venue
Nature Structural & Molecular Biology
Published
2008-08-24
Volume
15
Issue
9
Pages
932-938
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W2052057644
Cited by
99
References
40
Citations by year
2023: 3 · 2022: 4 · 2021: 9 · 2020: 3 · 2019: 3 · 2017: 4 · 2016: 2 · 2015: 9 · 2014: 6 · 2013: 7 · 2012: 10
FWCI
12.86
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Energy (W - 31 - 109 - Eng - 38)
  • National Institutes of Health (AI45086)
  • Office of Science (W-31-109-ENG-38)
  • National Institute of Allergy and Infectious Diseases (R21AI045086, AI45086, R01AI045086, Z01AI000881)
  • Basic Energy Sciences (W-31-109-Eng38)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
Keywords
VAR2CSA, chondroitin sulfate A, malaria in pregnancy, Plasmodium falciparum, Duffy binding-like domain, carbohydrate-protein interactions, binding sites, lysine residues, vaccine targets, placental malaria
MeSH terms
Animals, Antigens, Protozoan, Binding Sites, Chondroitin Sulfates, Erythrocytes, Female, Humans, Infant, Newborn, Models, Molecular, Placenta, Plasmodium falciparum, Pregnancy, Pregnancy Complications, Parasitic, Protozoan Proteins, Mutagenesis, Site-Directed, Malaria, Falciparum, Protein Structure, Tertiary, Crystallography, X-Ray, Macromolecular Substances, Static Electricity

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