title: Plasmodium falciparum erythrocyte membrane protein 1 is anchored to the actin-spectrin junction and knob-associated histidine-rich protein in the erythrocyte skeleton.
abstract: A distinctive pathological feature of Plasmodium falciparum malaria is the endothelial attachment of erythrocytes infected with mature asexual-stage parasites in microvessels of the major organs. Electron-dense protrusions described as knobs are displayed on the surface of parasitized erythrocytes and act as attachment points in cytoadherence. Parasite-encoded knob-associated histidine-rich protein (KAHRP) is a major component of knobs found on the cytoplasmic side of the host cell membrane. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of parasite-encoded cytoadherence receptors localized to knobs on the surface of parasitized erythrocytes. Despite its high antigenic diversity, PfEMP1 has a remarkably conserved cytoplasmic domain. We demonstrate in this study that the cytoplasmic domain of PfEMP1 (VAR(CD)) binds to host spectrin and actin and to full-length KAHRP in vitro. Apparent dissociation constants determined for VAR(CD)/F-actin and VAR(CD)/KAHRP interactions are 44.9+/-6.4 and 10. 7+/-2.2 nM, respectively. Further, we provide evidence that KAHRP polypeptides self-associate in solution to form structures similar to knobs and show binding of self-associated KAHRP clusters to spectrin-actin-protein 4.1 complexes. Findings in this study suggest that PfEMP1 is localized to the knob in P. falciparum-infected erythrocytes by binding to the host spectrin-actin junction and to self-associated KAHRP through its conserved cytoplasmic domain.
authors.affiliation: Department of Medicine, Section of Hematology-Oncology Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, 02135, Boston, MA, USA. stevenoh@semc.org
authors.forename: S S
authors.initials: SS
authors.lastname: Oh
authors.forename: S
authors.initials: S
authors.lastname: Voigt
authors.forename: D
authors.initials: D
authors.lastname: Fisher
authors.forename: S J
authors.initials: SJ
authors.lastname: Yi
authors.forename: P J
authors.initials: PJ
authors.lastname: LeRoy
authors.forename: L H
authors.initials: LH
authors.lastname: Derick
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: A H
authors.initials: AH
authors.lastname: Chishti
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004910:Erythrocyte Membrane / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism* / Q000472:pathogenicity / Q000502:physiology; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013049:Spectrin / Q000378:metabolism
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; C097699:MAK16 protein, S cerevisiae; D010455:Peptides; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C042968:knob protein, Plasmodium falciparum; D013049:Spectrin