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1.
BMC Genomics ; 8: 45, 2007 Feb 07.
Article in English | MEDLINE | ID: mdl-17286864

ABSTRACT

BACKGROUND: Var genes encode a family of virulence factors known as PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) which are responsible for both antigenic variation and cytoadherence of infected erythrocytes. Although these molecules play a central role in malaria pathogenesis, the mechanisms generating variant antigen diversification are poorly understood. To investigate var gene evolution, we compared the variant antigen repertoires from three geographically diverse parasite isolates: the 3D7 genome reference isolate; the recently sequenced HB3 isolate; and the IT4/25/5 (IT4) parasite isolate which retains the capacity to cytoadhere in vitro and in vivo. RESULTS: These comparisons revealed that only two var genes (var1csa and var2csa) are conserved in all three isolates and one var gene (Type 3 var) has homologs in IT4 and 3D7. While the remaining 50 plus genes in each isolate are highly divergent most can be classified into the three previously defined major groups (A, B, and C) on the basis of 5' flanking sequence and chromosome location. Repertoire-wide sequence comparisons suggest that the conserved homologs are evolving separately from other var genes and that genes in group A have diverged from other groups. CONCLUSION: These findings support the existence of a var gene recombination hierarchy that restricts recombination possibilities and has a central role in the functional and immunological adaptation of var genes.


Subject(s)
Antigens, Protozoan/genetics , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Animals , Chromosome Mapping , Evolution, Molecular , Genes, Protozoan , Genetic Variation , Genome, Protozoan , Phylogeny , Plasmodium falciparum/classification , Recombination, Genetic/genetics , Sequence Analysis, DNA
2.
Mol Biochem Parasitol ; 137(1): 55-64, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15279951

ABSTRACT

Cytoadherence of Plasmodium falciparum-infected erythrocytes is associated with severe malaria and is primarily mediated through binding of the variant surface antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1) to specific host ligands. Infected erythrocyte binding to Intercellular Adhesion Molecule 1 (ICAM-1) has been implicated as having a role in cerebral malaria, a major cause of death from P. falciparum infection. We have examined ICAM-1-binding PfEMP1 proteins in the cytoadhesive P. falciparum strain IT4/25/5 in order to extend our understanding of binding. For A4tres, the ICAM-1 binding region was previously shown to reside within contiguous DBL2beta and c2 domains. We determined the gene sequence encoding IT-ICAM var, and showed that ICAM-1 binding in this protein also maps to DBL2betac2 domains that have 48% amino acid identity to A4tres. By truncation and chimera analysis, most of the DBL2beta and the first half of the c2 region were required for A4tres binding to ICAM-1, suggesting this tandem should be considered a structural-functional combination for ICAM-1 binding. Of interest, a chimera formed between two different ICAM-1 binding domains did not bind ICAM-1, suggesting a functional interdependence between DBL2beta and c2 from the same protein. As gene recombination and gene conversion are important mechanisms for generating diversity in the PfEMP1 protein family, this finding implies an extra level of constraint on the functional evolution of binding traits. Knowledge about the PfEMP1::ICAM-1 interaction may allow the development of interventions to prevent binding and disease.


Subject(s)
Intercellular Adhesion Molecule-1/metabolism , Plasmodium falciparum/pathogenicity , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Amino Acid Sequence , Animals , Conserved Sequence , DNA, Protozoan/chemistry , Molecular Sequence Data , Plasmodium falciparum/genetics , Protein Binding , Protein Interaction Mapping , Protein Structure, Tertiary , Protozoan Proteins/genetics , Recombination, Genetic , Sequence Alignment , Sequence Analysis, DNA
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