A model of the complex between the PfEMP1 malaria protein and the human ICAM‐1 receptor

Abstract

Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium can infect humans: P. falciparum, P. malariae, P. vivax, and P. ovale. P. falciparum is the only able to cytoadhere to the surface of postcapillary endothelial cells. A key role in cytoadherence is played by the interaction between the PfEMP1 P. falciparum protein and the human intracellular adhesion molecule (ICAM-1) although very little is known about the molecular details of this complex. Here we propose a model for this interaction on the basis of a homology model of the functional domain of PfEMP1 and of the ICAM-1 three dimensional structures. Our model is consistent with the results of many experimental observations, provides a rational explanation for the different binding abilities of different strains of P. falciparum and explains the reduced binding affinity of the A4 strain of P. falciparum for the ICAM-1(Kilifi) polymorphism. On the basis of our model, we can also explain why the murine ICAM-1, although sharing 70% sequence similarity with its human homologue, does not bind PfEMP1, and why the binding of fibrinogen and PfEMP1 to ICAM-1 is mutually exclusive. The model of the complex proposed here can serve as a useful tool for the design and interpretation of biochemical and immunological experimental results.

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

“…In loop 3, a 3-amino acid motif containing a hydrophilic residue-hydrophobic residue-hydrophilic residue, is completely conserved in binding domains. The hydrophobic residue in this motif is Ile with a single conservative exception (Val in var16), and appears to be in close contact with the ICAM1 molecule in the model [32]. This residue is absent in 37% of non-binding sequences.…”

“…Figure S2 shows the alignment of DBLβC2 domains from both FCR3/IT and 3D7 strains, with four loops predicted to participate in ICAM1 contacts [32] indicated in boxes. We find that residues previously shown to be conserved in the ICAM1-binding DBL2βC2 domains of FCR3/IT are conserved in ICAM1-binding domain of 3D7 as well.…”

“…This was elegantly demonstrated by the Smith group [29], which examined amino acid substitutions and their combinations on ICAM1 binding by DBL2βC2 domains from two genes, var16 and var31 from FCR3/IT parasite. Using the model of DBL2βC2 complexed with ICAM1 [32] and the Deep View/Swiss-pdb viewer program (v.3.7), we examined the effect of replacing conserved Ala 286 with Tyr in loop 4. The substitution does not introduce any amino acid residue clashes, and may provide an additional intra-domain hydrogen bond to R 113 (data not shown).…”

“…Color font: Purple - conserved and semi-conserved residues, bold font indicates predominant residue; Blue - conserved and semi-conserved residues in ICAM1 binders, bold font indicates residues only in ICAM1 binders for emphasis; Red - amino acid residue substitution with significantly different physical-chemical character that may affect structure or/and function of the domain; Green - the only exception for position 3 in loop 4 in ICAM1-binding variant; Pink - amino acid residues that differ from the annotated sequence in PlasmoDB database. Red rectangles indicate four flexible loops involved in ICAM1 binding according to the modeling studies [32].…”

Senescent Sickle Erythrocytes and Endothelial Adhesion via Band 3 Peptides

“…As further proof, an in vivo study has shown that intravenous administration of band 3 peptides to monkeys infected by falciparum parasites is able to inhibit adhesion of their infected erythrocytes [8]. The reason for the endothelial adhesion in falciparum infections appears to be that the falciparum parasite is the only one of the four types of malaria parasites that have an additional adhesive molecule called the Plasmodium falciparum erythrocyte membrane protein 1 [10]. The reason for the endothelial adhesion of band 3 peptides in SCA is a work in progress and a recent study suggests that one factor may be that some of the band 3 adhesive peptides are not cloaked by antibodies.…”