X-ray Crystallography Used to Explore Placental Malaria's Chondroitin Sulfate-Binding Domain

People living in endemic countries develop partial immunity after multiple disease episodes, and this immunity correlates with acquisition of strain-specific antibodies that recognize PfEMP1 proteins. These proteins are expressed on the surface of infected red blood cells, where they bind to human receptors, sequestering the cells away from spleen-mediated destruction. This protects the parasite and prolongs the infection. These interactions also cause infected cells to accumulate in the brain and on the placenta during cerebral malaria and malaria of pregnancy, leading to some of the most deadly symptoms of the disease.

In malaria of pregnancy, domains from the var2csa-encoded PfEMP1 protein interact with chondroitin sulfate on the placenta surface. This causes accumulation of infected red blood cells, leading to placental inflammation and block of blood flow to the developing fetus. This is associated with maternal anemia, low birth weight, and premature delivery and can lead to the death of mother and child.

In the current study Dr. Matthew Higgins, professor of biochemistry at the University of Cambridge (UK) determined the structure of the DBL3X domain from a xenon derivative using single-wavelength dispersion data collected employing chromium K-alpha radiation that was refined to 0.18 nm resolution.

Results published in the August 8, 2008, issue of the Journal of Biological Chemistry (JBC) revealed that the domain adopted a fold similar to malarial invasion proteins, with extensive loop insertions. One loop was flexible in the unliganded structure but observed in the presence of sulfate or disaccharide, where it completed a sulfate-binding site. This loop, and others surrounding this putative carbohydrate-binding site, was flexible and polymorphic, perhaps protecting the binding site from immune detection.

This structure suggests a model for how the domain maintains ligand binding while evading the immune response and serves as a guide for future drug and vaccine development.

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