The 22 kDa component of the protein complex on the surface of Plasmodium falciparum merozoites is derived from a larger precursor, merozoite surface protein 7

Pachebat, Justin A.; Ling, Irene T.; Grainger, Munira; Trucco, Carlotta; Howell, Steven; Fernández-Reyes, Delmiro; Gunaratne, Ruwani S.; Holder, Anthony A.

doi:10.1016/s0166-6851(01)00336-x

Cited by 103 publications

(118 citation statements)

References 27 publications

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“…Among the surface antigens, Plasmodium merozoite surface protein-1 (MSP1) represents by far the most well-documented example of primary processing. Plasmodium falciparum MSP1 (PfMSP1) is an approximately 200 kDa surface antigen that forms a noncovalent complex with MSP6, MSP7 and MSP9 (Pachebat et al ., 2001;Trucco et al ., 2001;Li et al ., 2004). During or just before merozoite release (the precise timing has not been unambiguously established), MSP1 is proteolytically processed into fragments of 83, 30, 38 and 42 kDa (in order from the N-to C-terminus).…”

Section: Primed For Penetrationmentioning

confidence: 99%

A new release on life: emerging concepts in proteolysis and parasite invasion

Carruthers

Blackman²

2005

Molecular Microbiology

104

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SummaryCell invasion by apicomplexan pathogens such as the malaria parasite and Toxoplasma is accompanied by extensive proteolysis of zoite surface proteins (ZSPs) required for attachment and penetration. Although there is still little known about the proteases involved, a conceptual framework is emerging for the roles of proteolysis in cell invasion. Primary processing of ZSPs, which includes the trimming of terminal peptides or segmentation into multiple fragments, is proposed to activate these adhesive ligands for tight binding to host receptors. Secondary processing, which occurs during penetration, results in the shedding of ZSPs by one of two mechanistically distinct ways, shaving or capping. Resident surface proteins are typically shaved from the surface whereas adhesive ligands mobilized from intracellular secretory vesicles are capped to the posterior end of the parasite before being shed during the final steps of penetration. Intriguingly, recent studies have revealed that ZSPs can be released either by being cleaved adjacent to the membrane anchor or actually within the membrane itself. Mounting evidence suggests that intramembrane cleavage is catalysed by one or more integral membrane serine proteases of the Rhomboid family and we propose that several malaria adhesive ligands may be potential substrates for these enzymes. We also discuss the evidence that the key reason for ZSP shedding during invasion is to break the connection between parasite surface ligands and host receptors. The sequential proteolytic events associated with invasion by pathogenic protozoa may represent vulnerable pathways for the future development of synergistic anti-protozoal therapies.

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Section: Primed For Penetrationmentioning

confidence: 99%

A new release on life: emerging concepts in proteolysis and parasite invasion

Carruthers

Blackman²

2005

Molecular Microbiology

104

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“…MSP1 is an essential and abundant surface protein expressed during schizogony as an ϳ200-kDa precursor protein (30). Prior to the schizont rupture, MSP1 is proteolytically processed to produce the 83-, 30-, 38-, and 42-kDa fragments (31,36,38) that remain noncovalently associated along with MSP6, MSP7, and MSP9 (34,44,53) and tethered to the surface by the glycosylphosphatidylinositol (GPI)-anchored 42-kDa fragment (MSP1 42 ) (43,44). During invasion, MSP1 42 is further cleaved into MSP1 33 and MSP1 19 (25,26) to release the entire complex except for MSP1 19 that remains GPI anchored and is carried into the newly invaded red blood cell (RBC) (7,19).…”

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confidence: 99%

Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8

et al. 2012

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ABSTRACTThe C-terminal 19-kDa domain of merozoite surface protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using thePlasmodium yoeliimurine model, we fusedP. yoeliiMSP119(PyMSP119) with full-lengthP. yoeliimerozoite surface protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protectivePyMSP119- andPyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite,Plasmodium falciparum. Distinct fromPyMSP8,P. falciparumMSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-lengthPfMSP8 and a truncated version devoid of the Asn/Asp-rich domain,PfMSP8(ΔAsn/Asp), showed that both proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of nativePfMSP8 expression revealed thatPfMSP8 is present intracellularly in late schizonts and merozoites. Following invasion,PfMSP8 is found distributed on the surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression ofPfMSP8 on the surface of merozoites,PfMSP8-specific rabbit IgG did not inhibit thein vitrogrowth ofP. falciparumblood-stage parasites. These studies suggest that the further development ofPfMSP8 as a malaria vaccine component should focus on the use ofPfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, includingPfMSP119.

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“…MSP-7, which is a member of a multigene family, is highly conserved in P. falciparum, and homologues were identified in other parasite species (2,13). Because only a processed form of MSP-7 is found at the merozoite surface (14), it was proposed that conversion of MSP-7 into MSP-7 22 takes place prior to merozoite release.…”

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confidence: 99%

Interactions between Merozoite Surface Proteins 1, 6, and 7 of the Malaria ParasitePlasmodium falciparum

et al. 2006

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Merozoites of the malaria parasite Plasmodium falciparum expose at their surface a large multiprotein complex, composed of proteolytically processed, noncovalently associated products of at least three genes, msp-1, msp-6, and msp-7. During invasion of erythrocytes, this complex is shed from the surface except for a small glycosylphosphatidylinositol-anchored portion originating from MSP-1. The proteolytic cleavage separating the C-terminal portion of MSP-1 is required for successful invasion. Little is known about the structure and function of the abundant and essential multipartite complex. Using heterologously produced MSP-1, MSP-6, and MSP-7 in precursor and with the exception of MSP-7 in processed form, we have studied in vitro the complex formation between the different proteins to identify the interaction partners within the complex. Both MSP-6 36 and MSP-7 bind only to MSP-1 subunits that are shed, but although MSP-6 36 contacts just subunit p38, MSP-7 interacts with p83, p30, and p38. The intact C-terminal region of MSP-6 is required for the association with p38 as well as for its multimerization into tetramers. Furthermore, our data suggest that only the processed form and not the precursor form of MSP-1 interacts with MSP-6 36 . MSP-6-as well as MSP-7-specific rabbit antibodies inhibit parasite multiplication in vitro as shown previously for antibodies directed against MSP-1. Our findings raise interesting questions with regard to proteolysis-mediated mechanisms of maturation of the MSP-1-MSP-6-MSP-7 complex and to the mode by which antibodies directed against this complex interfere with parasite multiplication.

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The 22 kDa component of the protein complex on the surface of Plasmodium falciparum merozoites is derived from a larger precursor, merozoite surface protein 7

Cited by 103 publications

References 27 publications

A new release on life: emerging concepts in proteolysis and parasite invasion

A new release on life: emerging concepts in proteolysis and parasite invasion

Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8

Interactions between Merozoite Surface Proteins 1, 6, and 7 of the Malaria ParasitePlasmodium falciparum

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