Dataset Information

The structure of a chondroitin sulfate-binding domain important in placental malaria.

ABSTRACT: Adhesive PfEMP1 proteins are displayed on the surface of malaria-infected red blood cells. They play a critical role in the disease, tethering infected cells away from destruction by the spleen and causing many severe symptoms. A molecular understanding of how these domains maintain their binding properties while evading immune detection will be important in developing therapeutics. 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. Here I present the structure of the chondroitin sulfate-binding DBL3X domain from a var2csa-encoded PfEMP1 protein. The domain adopts a fold similar to malarial invasion proteins, with extensive loop insertions. One loop is flexible in the unliganded structure but observed in the presence of sulfate or disaccharide, where it completes a sulfate-binding site. This loop, and others surrounding this putative carbohydrate-binding site, are flexible and polymorphic, perhaps protecting the binding site from immune detection. This suggests a model for how the domain maintains ligand binding while evading the immune response and will guide future drug and vaccine development.

SUBMITTER: Higgins MK

PROVIDER: S-EPMC2494935 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The structure of a chondroitin sulfate-binding domain important in placental malaria.

Higgins Matthew K MK

The Journal of biological chemistry 20080611 32

Adhesive PfEMP1 proteins are displayed on the surface of malaria-infected red blood cells. They play a critical role in the disease, tethering infected cells away from destruction by the spleen and causing many severe symptoms. A molecular understanding of how these domains maintain their binding properties while evading immune detection will be important in developing therapeutics. In malaria of pregnancy, domains from the var2csa-encoded PfEMP1 protein interact with chondroitin sulfate on the ...[more]

PMID: 18550531

Similar Datasets

Project description:BackgroundPlacental malaria is typified by selective clustering of Plasmodium falciparum in the intervillous blood spaces of the placenta. Sequestration of malaria parasite in the human placenta is mediated by interactions between chondroitin sulphate A (CSA) on the syncytiotrophoblasts and proteins expressed on the surface of infected human erythrocytes. Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) encoded by the var2CSA gene is believed to be the main parasite ligand for CSA-mediated placental binding.MethodsExtensive sequence and structure comparisons of the various CSA-binding and non-binding DBL domains from the var2CSA gene from A4 and 3D7 strains of P. falciparum were performed. Three-dimensional structural models of various DBL domains were built and analysed with a view to assessing conservation of CSA interaction sites across various DBL domains.ResultsEach of the six DBL domains from var2CSA are likely to retain the disulfide linkages evident from previously published DBL domain crystal structures. The number of disulfide linkages between the various DBL domains analysed varies from three to seven, of which two are conserved across all DBL domains. The conserved disulfide linkages are distributed within the respective three sub-domains and only one linkage is shared by sub-domains I and II. Major differences between CSA-binding DBL domains are in the loop regions, which tie the alpha helices together, and in variable length terminal extensions. Intriguingly, a crucial loop from A4 DBL 3X which provides the important Gly and Lys residues that chelate the bound sulphate is missing or significantly altered in all other DBL domains that interact with CSA. Further analysis of the proposed sulphate and predicted CSA-binding site indicates either none or very low level of conservation among the critical interacting residues.ConclusionStructural comparisons of the three-dimensional structures of CSA-binding DBL domains indicates that the proposed CSA interaction site on A4 DBL 3X is unlikely to be conserved across the other CSA-binding DBL domains from var2CSA. Therefore, the 4 CSA-binding DBL domains encoded by var2CSA are unlikely to have common architectures to their CSA recognition sites. These structural insights have clear implications in using CSA-binding DBL domains for vaccines against placental malaria as it is proposed that the various CSA-binding DBL domains on var2CSA will recognize their CSA ligands differently.

Dataset Information

The structure of a chondroitin sulfate-binding domain important in placental malaria.

Publications

The structure of a chondroitin sulfate-binding domain important in placental malaria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure