Sequence similarity between the erythrocyte binding domain of the Plasmodium vivax Duffy binding protein
Background
The HIV surface glycoprotein gp120 (SU, gp120) and the Plasmodium vivax Duffy binding protein (PvDBP) bind to chemokine receptors during infection and have a site of amino acid sequence similarity in their binding domains that often includes a heparin binding motif (HBM). Infection by either pathogen has been found to be inhibited by polyanions.
Results
Specific polyanions that inhibit HIV infection and bind to the V3 loop of X4 strains also inhibited DBP-mediated infection of erythrocytes and DBP binding to the Duffy Antigen Receptor for Chemokines (DARC). A peptide including the HBM of PvDBP had similar affinity for heparin as RANTES and V3 loop peptides, and could be specifically inhibited from heparin binding by the same polyanions that inhibit DBP binding to DARC. However, some V3 peptides can competitively inhibit RANTES binding to heparin, but not the PvDBP HBM peptide. Three other members of the DBP family have an HBM sequence that is necessary for erythrocyte binding, however only the protein which binds to DARC, the P. knowlesi alpha protein, is inhibited by heparin from binding to erythrocytes. Heparitinase digestion does not affect the binding of DBP to erythrocytes.
Conclusion
The HBMs of DBPs that bind to DARC have similar heparin binding affinities as some V3 loop peptides and chemokines, are responsible for specific sulfated polysaccharide inhibition of parasite binding and invasion of red blood cells, and are more likely to bind to negative charges on the receptor than cell surface glycosaminoglycans.
Introduction
The human immunodeficiency virus type 1 (HIV-1), the human malaria, Plasmodium vivax, and the monkey malaria, P. knowlesi, have ligands that bind to chemokine receptors and mediate cell invasion. The surface glycoprotein gp120 (SU) of HIV-1 binds to CCR5 and CXCR4 as the major coreceptors for infecting CD4+ T-lymphocytes in vivo, and changes in the amino acid sequence of the V3 loop of gp120 can change viral tropism from CCR5 using (R5) to CXCR4 using (X4) to both (R5X4). The V3 loop region of gp120 also provides a neutralizing epitope, and can bind glycosaminoglycans and other polyanions which inhibit viral infection.
P. vivax uses a Duffy binding protein (PvDBP) to bind the Duffy antigen receptor for chemokines (DARC) and invade human reticulocytes. P. knowlesi has three proteins, the P. knowlesi α, β, and γ proteins which can mediate binding to rhesus erythrocytes, and the P. knowlesi α protein (PkDBP) can bind to human and rhesus DARC. PvDBP, PkDBP, P. knowlesi β, and γ proteins are members of a Duffy Binding Ligand (DBL) family of erythrocyte binding proteins with conserved regions of homology which bind to many receptors. Region II within the family, as defined by conserved cysteine residues, is responsible for erythrocyte binding, and region II of PkDBP has been shown to be inhibited by glycosaminoglycan binding.
In a separate report, we describe an amino acid sequence similarity between subdomain 1 in DBP region II and the V3 loop of HIV strain MN. Within subdomain 1 and this V3 loop are consensus BBXB heparin binding motifs (HBM), where B is a basic amino acid and X is any amino acid. This HBM is conserved in many DBL family members, and we previously found that alanine substitutions at this site in PvDBP and PkDBP abrogated DARC binding. RANTES is a natural ligand of both CCR5 and DARC and can inhibit both HIV and DBP binding to their respective receptors. SDF-1 is a natural ligand for CXCR4, and both RANTES and SDF-1 have HBM and are known to bind sulfated polysaccharides.