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      Conserved residues in the Plasmodium vivax Duffy-binding protein ligand domain are critical for erythrocyte receptor recognition

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      Proceedings of the National Academy of Sciences
      Proceedings of the National Academy of Sciences

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          Abstract

          Malaria merozoite invasion of human erythrocytes depends on recognition of specific erythrocyte surface receptors by parasite ligands. Plasmodium vivax merozoite invasion is totally dependent on the recognition of the Duffy blood group antigen by the parasite ligand Duffy-binding protein (DBP). Receptor recognition by P. vivax relies on a cysteine-rich domain, the DBL domain or region II, at the N terminus of the extracellular portion of DBP. The minimal region of the DBP implicated for receptor recognition lies between cysteines 4 and 8 of the DBL domain, which is a region that also has the highest rate of allelic polymorphisms among parasite isolates. We previously found that allelic polymorphisms in this region altered the P. vivax DBL domain antigenic character, which contrasts with changes in receptor specificity attributed to polymorphisms in some homologous ligands of Plasmodium falciparum. To further investigate the relative importance of conserved and polymorphic residues within this DBL central region, we identified residues critical for receptor recognition by site-directed mutagenesis. Seventy-seven surface-predicted residues of the Sal-1 DBL domain were substituted with alanine and assayed for erythrocyte binding activity by expression of the mutant proteins on the surface of transiently transfected COS cells. The functional effect of alanine substitution varied from nil to complete loss of DBL erythrocyte-binding activity. Mutations that caused loss of ligand function mostly occurred in discontinuous clusters of conserved residues, whereas nearly all mutations in polymorphic residues did not affect erythrocyte binding. These data delineate DBL domain residues essential for receptor recognition.

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          A family of erythrocyte binding proteins of malaria parasites.

          Malaria erythrocyte binding proteins use the Duffy blood group antigen (Plasmodium vivax and Plasmodium knowlesi) and sialic acid (Plasmodium falciparum) on the erythrocyte surface as receptors. We had previously cloned the one P. vivax gene, the one P. falciparum gene, and part of one of the three P. knowlesi genes encoding these erythrocyte binding proteins and described the homology between the P. knowlesi and P. vivax genes. We have completed the cloning and sequencing of the three P. knowlesi genes and identified introns in the P. vivax and P. falciparum genes that correct the previously published deduced amino acid sequences. All have similar structures, with one or two exons encoding the signal sequence and the erythrocyte binding domain, an exon encoding the transmembrane domain, and two exons encoding the cytoplasmic domain with the exception of the P. knowlesi beta gene. The regions of amino acid sequence homology among all the genes are the 5' and 3' cysteine-rich regions of the erythrocyte binding domain. On the basis of gene structure and amino acid homology, we propose that the Duffy binding proteins and the sialic acid binding protein are members of a gene family. The level of conservation (approximately 70%) of the deduced amino acid sequences in the 5' cysteine-rich region between the P. vivax protein and the three P. knowlesi proteins is as great as between the three P. knowlesi proteins themselves; the P. knowlesi beta protein just 3' to this cysteine-rich region is homologous to the P. vivax protein but not to the other P. knowlesi proteins. Conservation of amino acid sequences among these organisms, separated in evolution, may indicate the regions where the adhesin function resides.
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            Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion

            Plasmodium vivax and the related monkey malaria, P. knowlesi, require interaction with the Duffy blood group antigen, a receptor for a family of chemokines that includes interleukin 8, to invade human erythrocytes. One P. vivax and three P. knowlesi proteins that serve as erythrocyte binding ligands in such interactions share sequence homology. Expression of different regions of the P. vivax protein in COS7 cells identified a cysteine-rich domain that bound Duffy blood group-positive but not Duffy blood group-negative human erythrocytes. The homologous domain of the P. knowlesi proteins also bound erythrocytes, but had different specificities. The P. vivax and P. knowlesi binding domains lie in one of two regions of homology with the P. falciparum sialic acid binding protein, another erythrocyte binding ligand, indicating conservation of the domain for erythrocyte binding in evolutionarily distant malaria species. The binding domains of these malaria ligands represent potential vaccine candidates and targets for receptor-blockade therapy.
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              Invasion of erythrocytes by malaria merozoites.

              An electro-optical system was developed to record microscope images with high resolution at low light intensities. The system was used to study the invasion of erythrocytes by malaria merozoites. Invasion consists of attachment of the anterior end of the parasite to the erythrocyte, deformation of the erythrocyte, and the entry of the parasite by erythrocyte membrane invagination.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                November 02 2004
                November 02 2004
                October 21 2004
                November 02 2004
                : 101
                : 44
                : 15754-15759
                Article
                10.1073/pnas.0405421101
                524844
                15498870
                85fb1242-4cdb-4d0d-b896-1588ee2b9d21
                © 2004
                History

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