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J. Biol. Chem., Vol. 282, Issue 31, 22426-22436, August 3, 2007

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Structural Basis for Binding of Plasmodium falciparum Erythrocyte Membrane Protein 1 to Chondroitin Sulfate and Placental Tissue and the Influence of Protein Polymorphisms on Binding Specificity^*

James G. Beeson¹, Katherine T. Andrews, Michelle Boyle, Michael F. Duffy^¶, Ee Ken Choong^¶, Tim J. Byrne^¶, Joanne M. Chesson, Alexander M. Lawson^||, and Wengang Chai^||2

From the The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia, Clinical Tropical Medicine Laboratory and the Griffith Medical Research College, Queensland Institute of Medical Research, Queensland 4066, Australia, ^¶Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia, and ^||Glycosciences Laboratory, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, Middlesex HA1 3UJ, United Kingdom

Chondroitin sulfate (CS) A is a key receptor for adhesion of Plasmodium falciparum-infected erythrocytes (IEs) in the placenta and can also mediate adhesion to microvascular endothelial cells. IEs that adhere to CSA express var2csa-type genes, which encode specific variants of the IE surface antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1). We report direct binding of native PfEMP1, isolated from IEs and encoded by var2csa, to immobilized CSA. Binding of PfEMP1 was dependent on 4-O-sulfated disaccharides and glucuronic acid rather than iduronic acid, consistent with the specificity of intact IEs. Using immobilized CS oligosaccharides as neoglycolipid probes, the minimum chain length for direct binding of PfEMP1 was eight monosaccharide units. Similarly for IE adhesion to placental tissue there was a requirement for 4-O-sulfated GalNAc and glucuronic acid mixed with non-sulfated disaccharides; 6-O-sulfation interfered with the interaction between placental CSA and IEs. The minimum chain length for maximal inhibition of adhesion was 10 monosaccharide residues. Partially 4-O-sulfated CS oligosaccharides (45–55% sulfation) were highly effective inhibitors of placental adhesion (IC₅₀, 0.15 µg/ml) and may have potential for therapeutic development. We used defined P. falciparum isolates expressing different variants of var2csa in adhesion assays and found that there were isolate-specific differences in the preferred structural motifs for adhesion to CSA that correlated with polymorphisms in PfEMP1 encoded by var2csa-type genes. This may influence sites of IE sequestration or parasite virulence. These findings have significant implications for understanding the pathogenesis and biology of malaria, particularly during pregnancy, and the development of targeted interventions.

Received for publication, January 9, 2007 , and in revised form, June 6, 2007.

^* This work was supported by funding from the National Health and Medical Research Council, Australia (project grant and program grant; Career Development Award (to J. G. B.)); the Miller Fellowship of The Walter and Eliza Hall Institute (to J. G. B.); the Medical Research Council (Program Grant G9601454), UK; and a Griffith University research grant (to K. T. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ To whom correspondence may be addressed: The Walter and Eliza Hall Inst. of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Tel.: 61-3-9345-2555; Fax: 61-3-9347-0842; E-mail: beeson{at}wehi.edu.au. ² To whom correspondence may be addressed. Tel.: 44-20-8869-3255; Fax: 44-20-8869-3455; E-mail: w.chai{at}imperial.ac.uk.

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				J. G. Beeson, S. V. Madhunapantula, R. N. Achur, and D. C. Gowda Characteristics of Plasmodium falciparum-Infected-Erythrocyte Adhesion to Chondroitin Sulfate Infect. Immun., June 1, 2008; 76(6): 2808 - 2809. [Full Text] [PDF]