A family of chimeric erythrocyte binding proteins of malaria parasites

Abstract

Proteins sequestered within organelles of the apical complex of malaria merozoites are involved in erythrocyte invasion, but few of these proteins and their interaction with the host erythrocyte have been characterized. In this report we describe MAEBL, a family of erythrocyte binding proteins identified in the rodent malaria parasites Plasmodium yoelii yoelii and Plasmodium berghei. MAEBL has a chimeric character, uniting domains from two distinct apical organelle protein families within one protein. MAEBL has a molecular structure homologous to the Duffy binding-like family of erythrocyte binding proteins located in the micronemes of merozoites. However, the amino cysteine-rich domain of MAEBL has no similarity to the consensus Duffy binding-like amino cysteine-rich ligand domain, but instead is similar to the 44-kDa ectodomain fragment of the apical membrane antigen 1 (AMA-1) rhoptry protein family. MAEBL has a tandem duplication of this AMA-1-like domain, and both of these cysteine-rich domains bound erythrocytes when expressed in vitro. Differential transcription and splicing of the maebl locus occurred in the YM clone of P. yoelii yoelii. The apical distribution of MAEBL suggested localization within the rhoptry organelles of the apical complex. We propose that MAEBL is a member of a highly conserved family of erythrocyte binding proteins of Plasmodium involved in host cell invasion.Malaria merozoites enter erythrocytes by an active invasion process mediated by parasite ligands interacting with erythrocyte receptors (1, 2). Within minutes after release into the blood a free merozoite must recognize and enter an erythrocyte to ensure maintenance of the blood-stage infection. Mediators of the invasion process are positioned on the merozoite surface and in the organelles of the apical complex (micronemes, rhoptries, dense granules) when the merozoites mature in the schizont (3).A key step early in host cell invasion and a principal determinant of host cell specificity is the irreversible commitment of the merozoite to the selected host cell by the formation of a junction between merozoite and erythrocyte (4, 5). Junction formation is mediated by the Duffy binding-like (DBL) family of homologous erythrocyte binding proteins (EBPs) located within the micronemes of merozoites. The DBL-EBP family includes the Plasmodium vivax/Plasmodium knowlesi Duffy antigen binding proteins (DBPs) and the Plasmodium falciparum erythrocyte binding antigen 175 (EBA-175) (6-8). The similarity among DBL-EBPs is most prominent in two cysteine-rich domains, designated amino cysteine-rich domain and carboxyl cysteine-rich domain (6). The amino cysteine-rich domain is the principal adhesion domain binding to the erythrocyte receptors (9, 10), but the carboxyl cysteine-rich domain has no clear function, although the high degree of amino acid conservation among Plasmodium species suggests that this domain is important.Apical membrane antigen 1 (AMA-1) is a highly conserved apical organelle protein (11) thought to be involved in a...

Targeted disruption of maebl in Plasmodium falciparum

“…MAEBL is a paralogue of the DBL-EBP family (Duffy binding like-erythrocyte binding protein), but has a chimerical structure and shares similarity with AMA1 [3]. M1 and M2 are tandem cysteine-rich regions with similarity to AMA1 and are present in the N-terminal portion of the MAEBL ectodomain.…”

“…M1 and M2 are tandem cysteine-rich regions with similarity to AMA1 and are present in the N-terminal portion of the MAEBL ectodomain. MAEBL was identified in P. yoelii and P. falciparum blood stage parasites as a minor membrane protein with erythrocyte binding activity expressed in the apical organelles and on the surface of invasive merozoites [3][4][5][6]. Expressed abundantly in sporozoites, MAEBL appears to be important for sporozoite invasion into the mosquito salivary glands and in establishing exoerythrocytic schizonts [6][7][8][9][10][11][12].…”

Antibodies against MAEBL Ligand Domains M1 and M2 Inhibit Sporozoite Development In Vitro

“…While even though TRAP is essential for invasion of hepatocytes, antibodies against this transmembrane protein were shown not to inhibit sporozoite development into the exoerythrocytic stages. Therefore, it is important to identify additional sporozoite antigens that are potential targets for development as part of a multivalent pre-erythrocytic vaccine.MAEBL was identified in Plasmodium yoelii and P. falciparum blood-stage parasites as a minor type 1 membrane protein with erythrocyte binding activity expressed in the apical organelles and on the surface of invasive merozoites, but it was later identified as an abundant protein expressed in sporozoites (4,6,(8)(9)(10)(11)17). …”

“…MAEBL was identified in Plasmodium yoelii and P. falciparum blood-stage parasites as a minor type 1 membrane protein with erythrocyte binding activity expressed in the apical organelles and on the surface of invasive merozoites, but it was later identified as an abundant protein expressed in sporozoites (4,6,(8)(9)(10)(11)17). MAEBL is a paralogue of the products from the ebl family, similar except that its two extracellular ligand domains have identity to apical membrane antigen 1 and not the consensus Duffy binding-like ligand domains of other ebl products (10).…”

“…MAEBL is a paralogue of the products from the ebl family, similar except that its two extracellular ligand domains have identity to apical membrane antigen 1 and not the consensus Duffy binding-like ligand domains of other ebl products (10). The ebl family of erythrocyte binding proteins includes some of the best-characterized malarial ligands, such as the Plasmodium vivax Duffy binding protein and the P. falciparum erythrocyte binding protein EBA-175 (1).…”