title: Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A.
abstract: Plasmodium falciparum-infected erythrocytes adhere dichotomously to the host receptors CD36 and chondroitin sulfate A (CSA). This dichotomy is associated with parasite sequestration to microvasculature beds (CD36) or placenta (CSA), leading to site-specific pathogenesis. Both properties are mediated by members of the variant P. falciparum erythrocyte membrane protein 1 (PfEMP-1) family and reside on nonoverlapping domains of the molecule. To identify the molecular basis for the apparent dichotomy, we expressed various domains of PfEMP-1 individually or in combination and tested their binding properties. We found that the CD36-binding mode of the cysteine-rich interdomain region-1 (CIDR1) ablates the ability of the Duffy binding-like gamma domain to bind CSA. In contrast, neither a non-CD36-binding CIDR1 nor an intercellular adhesion molecule 1 binding domain had any affect on CSA binding. Our findings point out that interactions between different domains of PfEMP-1 can alter the adhesion phenotype of infected erythrocytes and provide a molecular basis for the apparent dichotomy in adhesion. We suggest that the basis for the dichotomy is structural and that mutually exclusive conformations of PfEMP-1 are involved in binding to CD36 or CSA. Furthermore, we propose a model explaining the requirement for structural dichotomy between placental and nonplacental isolates.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. bgamain@niaid.nih.gov
authors.forename: Benoit
authors.initials: B
authors.lastname: Gamain
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gratepanche
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
authors.forename: Dror I
authors.initials: DI
authors.lastname: Baruch
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000502:physiology*; D016466:CHO Cells; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000502:physiology*; D006224:Cricetinae; D004910:Erythrocyte Membrane / Q000469:parasitology; D004912:Erythrocytes / Q000469:parasitology*; D014644:Genetic Variation; D008322:Mammals; D016296:Mutagenesis; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D002809:Chondroitin Sulfates