Download MendeleyStructure of a Plasmodium Falciparum Pfemp1 Rosetting Domain Reveals a Role for the N-Terminal Segment in Heparin-Mediated Rosette Inhibition.
Juillerat, A., Lewit-Bentley, A., Guillotte, M., Gangnard, S., Hessel, A., Baron, B., Vigan-Womas, I., England, P., Mercereau-Puijalon, O., Bentley, G.A.(2011) Proc Natl Acad Sci U S A 108: 5243
- PubMed: 21402930
- DOI: https://doi.org/10.1073/pnas.1018692108
- Primary Citation of Related Structures:
2XU0 - PubMed Abstract:
The human malaria parasite Plasmodium falciparum can cause infected red blood cells (iRBC) to form rosettes with uninfected RBC, a phenotype associated with severe malaria. Rosetting is mediated by a subset of the Plasmodium falciparum membrane protein 1 (PfEMP1) variant adhesins expressed on the infected host-cell surface. Heparin and other sulfated oligosaccharides, however, can disrupt rosettes, suggesting that therapeutic approaches to this form of severe malaria are feasible. We present a structural and functional study of the N-terminal domain of PfEMP1 from the VarO variant comprising the N-terminal segment (NTS) and the first DBL domain (DBL1α(1)), which is directly implicated in rosetting. We demonstrate that NTS-DBL1α(1)-VarO binds to RBC and that heparin inhibits this interaction in a dose-dependent manner, thus mimicking heparin-mediated rosette disruption. We have determined the crystal structure of NTS-DBL1α(1), showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1α domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL α-class domain, is thus an intrinsic structural and functional component of the N-terminal VarO domain. The specific interaction observed with heparin opens the way for developing antirosetting therapeutic strategies.
Organizational Affiliation:
Institut Pasteur, Unité d'Immunologie Structurale, 75015 Paris, France.
