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A multidomain adhesion protein family expressed in Plasmodium falciparum is essential for transmission to the mosquito.

Pradel G, Hayton K, Aravind L, Iyer LM, Abrahamsen MS, Bonawitz A, Mejia C, Templeton TJ - J. Exp. Med. (2004)

Bottom Line: Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes.PfCCp expression markedly decreased after formation of zygotes.Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.

ABSTRACT
The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markers. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage-specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane-associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.

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Domain organization of the apicomplexan LCCL domain–containing gene family in P. falciparum (designated with prefix Pf) and orthologues present in C. parvum (designated with prefix Cp). All proteins have a signal peptide sequence represented by a black box at the beginning of the architectures. Ric, ricin domain; Disc, discoidin domain; A, ApicA domain; Anth, anthrax toxin NH2-terminal region domain; FN2, fibronectin type II domain; LCCL, Limulus coagulation factor C domain; Lev, levanase domain; LH, lipoxygenase domain; NEC, neurexins and collagens domain; SR, scavenger receptor domain.
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fig1: Domain organization of the apicomplexan LCCL domain–containing gene family in P. falciparum (designated with prefix Pf) and orthologues present in C. parvum (designated with prefix Cp). All proteins have a signal peptide sequence represented by a black box at the beginning of the architectures. Ric, ricin domain; Disc, discoidin domain; A, ApicA domain; Anth, anthrax toxin NH2-terminal region domain; FN2, fibronectin type II domain; LCCL, Limulus coagulation factor C domain; Lev, levanase domain; LH, lipoxygenase domain; NEC, neurexins and collagens domain; SR, scavenger receptor domain.

Mentions: Annotation of apicomplexan genomes reveals numerous genes encoding extracellular proteins having multidomain architectures reminiscent of, but in no case identical to, extracellular proteins found in multicellular organisms. We have recently conducted a whole genome comparison of P. falciparum and C. parvum genome sequences (unpublished data) and have exhaustively identified genes remarkable for multidomain “animal-like” architectures, in some instances conserved in orthologues present across the apicomplexan clade. Five of these proteins exhibit striking multiple adhesion modules and are herein grouped based upon the presence of a shared LCCL-like domain. The P. falciparum versions were accordingly termed PfCCp1 through PfCCp5 (see schematic in Fig. 1). PCCp3 has recently been variously described as PSLAP in P. falciparum and as PbSR in P. berghei to highlight the presence of tandem SR-like domains in addition to four copies of the LCCL domain (3, 4). CCp orthologues are conserved in C. parvum, as well as across the Plasmodium clade, with versions identified in the Plasmodium yoelii genome sequence and isolation of P. berghei versions, including PbCCp2 (sequence data are available from GenBank/EMBL/DDBJ under accession no. AF491294) and PbCCp3 (PbSR; GenBank/EMBL/DDBJ under accession no. AY034780). All PCCp genes possess signal peptide sequences as predicted by the SignalP algorithm (11). Transmembrane domains were not identified in PfCCp1 through PfCCp5, as predicted by the TMHMM2 program (12), nor are GPI anchor signal sequences present. Thus, given the predicted signal peptides, lack of ER retention or other organelle trafficking signals and the presence of disulfide bond containing extracellular adhesive domains combine to suggest that all PCCp proteins are secreted and serve extracellular functions, perhaps in parasite–parasite or parasite–host interactions.


A multidomain adhesion protein family expressed in Plasmodium falciparum is essential for transmission to the mosquito.

Pradel G, Hayton K, Aravind L, Iyer LM, Abrahamsen MS, Bonawitz A, Mejia C, Templeton TJ - J. Exp. Med. (2004)

Domain organization of the apicomplexan LCCL domain–containing gene family in P. falciparum (designated with prefix Pf) and orthologues present in C. parvum (designated with prefix Cp). All proteins have a signal peptide sequence represented by a black box at the beginning of the architectures. Ric, ricin domain; Disc, discoidin domain; A, ApicA domain; Anth, anthrax toxin NH2-terminal region domain; FN2, fibronectin type II domain; LCCL, Limulus coagulation factor C domain; Lev, levanase domain; LH, lipoxygenase domain; NEC, neurexins and collagens domain; SR, scavenger receptor domain.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211786&req=5

fig1: Domain organization of the apicomplexan LCCL domain–containing gene family in P. falciparum (designated with prefix Pf) and orthologues present in C. parvum (designated with prefix Cp). All proteins have a signal peptide sequence represented by a black box at the beginning of the architectures. Ric, ricin domain; Disc, discoidin domain; A, ApicA domain; Anth, anthrax toxin NH2-terminal region domain; FN2, fibronectin type II domain; LCCL, Limulus coagulation factor C domain; Lev, levanase domain; LH, lipoxygenase domain; NEC, neurexins and collagens domain; SR, scavenger receptor domain.
Mentions: Annotation of apicomplexan genomes reveals numerous genes encoding extracellular proteins having multidomain architectures reminiscent of, but in no case identical to, extracellular proteins found in multicellular organisms. We have recently conducted a whole genome comparison of P. falciparum and C. parvum genome sequences (unpublished data) and have exhaustively identified genes remarkable for multidomain “animal-like” architectures, in some instances conserved in orthologues present across the apicomplexan clade. Five of these proteins exhibit striking multiple adhesion modules and are herein grouped based upon the presence of a shared LCCL-like domain. The P. falciparum versions were accordingly termed PfCCp1 through PfCCp5 (see schematic in Fig. 1). PCCp3 has recently been variously described as PSLAP in P. falciparum and as PbSR in P. berghei to highlight the presence of tandem SR-like domains in addition to four copies of the LCCL domain (3, 4). CCp orthologues are conserved in C. parvum, as well as across the Plasmodium clade, with versions identified in the Plasmodium yoelii genome sequence and isolation of P. berghei versions, including PbCCp2 (sequence data are available from GenBank/EMBL/DDBJ under accession no. AF491294) and PbCCp3 (PbSR; GenBank/EMBL/DDBJ under accession no. AY034780). All PCCp genes possess signal peptide sequences as predicted by the SignalP algorithm (11). Transmembrane domains were not identified in PfCCp1 through PfCCp5, as predicted by the TMHMM2 program (12), nor are GPI anchor signal sequences present. Thus, given the predicted signal peptides, lack of ER retention or other organelle trafficking signals and the presence of disulfide bond containing extracellular adhesive domains combine to suggest that all PCCp proteins are secreted and serve extracellular functions, perhaps in parasite–parasite or parasite–host interactions.

Bottom Line: Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes.PfCCp expression markedly decreased after formation of zygotes.Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.

ABSTRACT
The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markers. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage-specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane-associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.

Show MeSH
Related in: MedlinePlus