title: Molecular architecture of a complex between an adhesion protein from the malaria parasite and intracellular adhesion molecule 1.
abstract: The adhesion of Plasmodium falciparum-infected erythrocytes to human tissues or endothelium is central to the pathology caused by the parasite during malaria. It contributes to the avoidance of parasite clearance by the spleen and to the specific pathologies of cerebral and placental malaria. The PfEMP1 family of adhesive proteins is responsible for this sequestration by mediating interactions with diverse human ligands. In addition, as the primary targets of acquired, protective immunity, the PfEMP1s are potential vaccine candidates. PfEMP1s contain large extracellular ectodomains made from CIDR (cysteine-rich interdomain regions) and DBL (Duffy-binding-like) domains and show extensive variation in sequence, size, and domain organization. Here we use biophysical methods to characterize the entire ∼300-kDa ectodomain from IT4VAR13, a protein that interacts with the host receptor, intercellular adhesion molecule-1 (ICAM-1). We show through small angle x-ray scattering that IT4VAR13 is rigid, elongated, and monomeric. We also show that it interacts with ICAM-1 through the DBLβ domain alone, forming a 1:1 complex. These studies provide a first low resolution structural view of a PfEMP1 ectodomain in complex with its ligand. They show that it combines a modular domain arrangement consisting of individual ligand binding domains, with a defined higher order architecture that exposes the ICAM-1 binding surface to allow adhesion.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Stig
authors.initials: S
authors.lastname: Christoffersen
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Andrews
authors.forename: Tadge
authors.initials: T
authors.lastname: Szestak
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Sine
authors.initials: S
authors.lastname: Larsen
authors.forename: Alister G
authors.initials: AG
authors.lastname: Craig
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
mesh_terms: D000818:Animals; D001665:Binding Sites; D001703:Biophysics / Q000379:methods; D002448:Cell Adhesion; D002942:Circular Dichroism; D004912:Erythrocytes / Q000469:parasitology; D006358:Hot Temperature; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008288:Malaria / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry; D012542:Scattering, Radiation; D020349:Surface Plasmon Resonance; D013696:Temperature; D014461:Ultracentrifugation; D014965:X-Rays
chemical_list: D008024:Ligands; D015800:Protozoan Proteins; D018799:Intercellular Adhesion Molecule-1