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J. Biol. Chem., Vol. 279, Issue 21, 21824-21832, May 21, 2004

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A Binding Site for Highly Sulfated Heparan Sulfate Is Identified in the N Terminus of the Circumsporozoite Protein

SIGNIFICANCE FOR MALARIAL SPOROZOITE ATTACHMENT TO HEPATOCYTES^*

John B. Ancsin and Robert Kisilevsky

From the Department of Pathology and Molecular Medicine, Queen's University and the Syl and Molly Apps Research Center, Kingston General Hospital, Kingston, Ontario Canada, K7L 3N6

Circumsporozoite protein (CSP) coats the malarial sporozoite and functions to target the liver for infection, which is the first step to developing malaria. An important tissue ligand for CSP is the glycosaminoglycan heparan sulfate (HS) found on the surface of hepatocytes and in the basement membrane of the space of Disse. To better understand this efficient targeting process, we set out to identify and characterize the HS binding site(s) of CSP. We synthesized a series of peptides corresponding to five regions of Plasmodium falciparum CSP containing basic residues, a common requirement of HS binding sites, and screened them for heparin and HS binding activity. Only one of these peptides (Pf 2), which contains a motif we have named region I-plus, demonstrated both high affinity heparin/HS binding activity and the ability to block the binding of recombinant CSP to heparin-Sepharose 4B. Analysis by isothermal titration calorimetry revealed that region I-plus has a binding constant of K_d = 5.0 µM and a stoichiometry of n = 7.8 binding sites/heparin chain. Heparin binding was dependent on the amino acid sequence of region I-plus, and the binding sites on heparin/HS are contained within a decasaccharide. Furthermore, HS oligosaccharides rich in sulfate and iduronic acid content (heparin-like) are required for efficient binding. Because liver HS is exceptionally high in both these components relative to the HS of other organs, the HS structural requirements for efficient region I-plus/HS binding are consistent with this peptide sequence functioning to target sporozoites to the liver for attachment to hepatocytes. Finally, the region I-plus heparin/HS binding site was also discovered for two other species that infect humans, Plasmodium malariae and Plasmodium vivax, further supporting the existence of a HS binding domain in the N-terminal portion of CSP.

Received for publication, February 23, 2004 , and in revised form, February 26, 2004.

^* This work was supported by a grant from the Bill and Melinda Gates Foundation. 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.

Recipient of a Detweiler Traveling Fellowship from the Royal College of Physicians and Surgeons of Canada during the execution of this work.

To whom correspondence should be addressed: Dept. of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada. Tel.: 613-548-6048; Fax: 613-533-2907; E-mail: 3jba1{at}post.queensu.ca.

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