title: Semaphorin-7A is an erythrocyte receptor for P. falciparum merozoite-specific TRAP homolog, MTRAP.
abstract: The motility and invasion of Plasmodium parasites is believed to require a cytoplasmic actin-myosin motor associated with a cell surface ligand belonging to the TRAP (thrombospondin-related anonymous protein) family. Current models of invasion usually invoke the existence of specific receptors for the TRAP-family ligands on the surface of the host cell; however, the identities of these receptors remain largely unknown. Here, we identify the GPI-linked protein Semaphorin-7A (CD108) as an erythrocyte receptor for the P. falciparum merozoite-specific TRAP homolog (MTRAP) by using a systematic screening approach designed to detect extracellular protein interactions. The specificity of the interaction was demonstrated by showing that binding was saturable and by quantifying the equilibrium and kinetic biophysical binding parameters using surface plasmon resonance. We found that two MTRAP monomers interact via their tandem TSR domains with the Sema domains of a Semaphorin-7A homodimer. Known naturally-occurring polymorphisms in Semaphorin-7A did not quantitatively affect MTRAP binding nor did the presence of glycans on the receptor. Attempts to block the interaction during in vitro erythrocyte invasion assays using recombinant proteins and antibodies showed no significant inhibitory effect, suggesting the inaccessibility of the complex to proteinaceous blocking agents. These findings now provide important experimental evidence to support the model that parasite TRAP-family ligands interact with specific host receptors during cellular invasion.
authors.affiliation: Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom ; Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: S Josefin
authors.initials: SJ
authors.lastname: Bartholdson
authors.forename: Leyla Y
authors.initials: LY
authors.lastname: Bustamante
authors.forename: Cecile
authors.initials: C
authors.lastname: Crosnier
authors.forename: Steven
authors.initials: S
authors.lastname: Johnson
authors.forename: Susan
authors.initials: S
authors.lastname: Lea
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D011110:Polymorphism, Genetic; D055503:Protein Multimerization / Q000235:genetics; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D015800:Protozoan Proteins; C118753:SEMA7A protein, human; D039961:Semaphorins