Evolutionary relationships of conserved cysteine-rich motifs in adhesive molecules of malaria parasites

• Published in: Molecular biology and evolution 2002-07, Vol.19 (7), p.1128-1142
• Main Authors: Michon, Pascal, Stevens, Jamie R, Kaneko, Osamu, Adams, John H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, Protozoan; Binding Sites; Blotting, Southern; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Adhesion - physiology; Cloning, Molecular; Cysteine - chemistry; DNA Primers - chemistry; Duffy Blood-Group System - genetics; Duffy Blood-Group System - metabolism; Erythrocytes - metabolism; Evolution, Molecular; Humans; Malaria - genetics; Malaria - metabolism; Molecular Sequence Data; Phylogeny; Plasmodium knowlesi - genetics; Plasmodium knowlesi - metabolism; Plasmodium vivax - genetics; Plasmodium vivax - metabolism; Polymerase Chain Reaction; Protein Binding; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Sequence Homology, Amino Acid
• ISSN: 0737-4038; 1537-1719
• DOI: 10.1093/oxfordjournals.molbev.a004171

Malaria parasites invade erythrocytes in a process mediated by a series of molecular interactions. Invasion of human erythrocytes by Plasmodium vivax is dependent upon the presence of a single receptor, but P. falciparum, as well as some other species, exhibits the ability to utilize multiple alternative invasion pathways. Conserved cysteine-rich domains play important roles at critical times during this invasion process and at other stages in the life cycle of malaria parasites. Duffy-binding-like (DBL) domains, expressed as a part of the erythrocyte-binding proteins (DBL-EBP), are such essential cysteine-rich ligands that recognize specific host cell surface receptors. DBL-EBP, which are products of the erythrocyte-binding-like (ebl) gene family, act as critical determinants of erythrocyte specificity and are the best-defined ligands from invasive stages of malaria parasites. The ebl genes include the P. falciparum erythrocyte-binding antigen-175 (EBA-175) and P. vivax Duffy-binding protein. DBL domains also mediate cytoadherence as a part of the variant erythrocytic membrane protein-1 (PfEMP-1) antigens expressed from var genes on the surface of P. falciparum-infected erythrocytes. A paralogue of the ebl family is the malarial ligand MAEBL, which has a chimeric structure where the DBL domain is functionally replaced with a distinct cysteine-rich erythrocyte-binding domain with similarity to the apical membrane antigen-1 (AMA-1) ligand domain. The Plasmodium AMA-1 ligand domain, which encompasses the extracellular cysteine domains 1 and 2 and is well conserved in a Toxoplasma gondii AMA-1, has erythrocyte-binding activity distinct from that of MAEBL. These important families of Plasmodium molecules (DBL-EBP, PfEMP-1, MAEBL, AMA-1) are interrelated through the MAEBL. Because MAEBL and the other ebl products have the characteristics expected of homologous ligands involved in equivalent alternative invasion pathways to each other, we sought to better understand their roles during invasion by determining their relative origins in the Plasmodium genome. An analysis of their multiple cysteine-rich domains permitted a unique insight into the evolutionary development of PLASMODIUM: Our data indicate that maebl, ama-1, and ebl genes have ancient origins which predate Plasmodium speciation. The maebl evolved as a single locus, including its unique chimeric structure, in each Plasmodium species, in parallel with the ama-1 and the ebl genes families. The ancient cha