Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for carbohydrate binding.

Abstract

VAR2CSA is the placental-malaria-specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.

• Authors: Maria C Bewley, Lovely Gautam, Mashanipalya G Jagadeeshaprasad, D Channe Gowda, John M Flanagan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 52 Pg. 18589-18603 (12 25 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 33122198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2020 Bewley et al.

Chemical References

• Antigens, Protozoan
• Glycosaminoglycans
• VAR2CSA protein, Plasmodium falciparum

Topics

• Antigens, Protozoan (chemistry, metabolism)
• Crystallography, X-Ray
• Female
• Glycosaminoglycans (metabolism)
• Humans
• Models, Molecular
• Placenta (metabolism)
• Plasmodium falciparum (metabolism)
• Pregnancy
• Protein Binding
• Protein Conformation
• Protein Domains