The merozoite surface protein 6 gene codes for a 36 kDa protein associated with the Plasmodium falciparum merozoite surface protein-1 complex

Trucco, Carlotta; Fernández-Reyes, Delmiro; Howell, Steven; Stafford, William; Scott-Finnigan, Terry J.; Grainger, Munira; Ogun, Solabomi A.; Taylor, William R.; Holder, Anthony A.

doi:10.1016/s0166-6851(00)00350-9

Cited by 111 publications

(102 citation statements)

References 54 publications

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“…The existence of a noncovalently associated complex of merozoite surface proteins including MSP6 36 , MSP7 22 , and processing products of MSP1 has been previously reported (32)(33)(34)40). Moreover, published evidence indicates that soluble proteins in the parasitophorous vacuole such as MSP3 (25,30), MSP9 (acidic basic repeat antigen) (19,25), and S-antigen (41,42) are also associated with the merozoite surface presumably by forming a direct or indirect noncovalent complex with a membrane-anchored merozoite surface protein.…”

Section: Discussionmentioning

confidence: 89%

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A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3

Chen

et al. 2004

Journal of Biological Chemistry

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In Plasmodium falciparum malaria, erythrocyte invasion by circulating merozoites may occur via two distinct pathways involving either a sialic acid-dependent or -independent mechanism. Earlier, we identified two nonglycosylated exofacial regions of erythrocyte band 3 termed 5ABC and 6A as an important host receptor in the sialic acid-independent invasion pathway. 5ABC, a major segment of this receptor, interacts with the 42-kDa processing product of merozoite surface protein 1 (MSP1 42 ) through its 19-kDa C-terminal domain. Here, we show that two regions of merozoite surface protein 9 (MSP9), also known as acidic basic repeat antigen, interact directly with 5ABC during erythrocyte invasion by P. falciparum. Native MSP9 as well as recombinant polypeptides derived from two regions of MSP9 (MSP9/⌬1 and MSP9/⌬2) interacted with both 5ABC and intact erythrocytes. Soluble 5ABC added to the assay mixture drastically diminished the binding of MSP9 to erythrocytes. Recombinant MSP9/⌬1 and MSP9/⌬2 present in the culture medium blocked P. falciparum reinvasion into erythrocytes in vitro. Native MSP9 and MSP1 42 , the two ligands binding to the 5ABC receptor, existed as a stable complex. Our results establish a novel concept wherein the merozoite exploits a specific complex of co-ligands on its surface to target a single erythrocyte receptor during invasion. This new paradigm poses a new challenge in the development of a vaccine for blood stage malaria.

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Section: Discussionmentioning

confidence: 89%

“…5A). MSP9 and perhaps MSP3 (25,30,31) could be a part of the previously identified merozoite protein complex containing MSP6 36 (32) and MSP7 22 (33,34), believed to be attached to the merozoite surface through the interaction with glycosyl phosphatidylinositol-anchored MSP1 42 .…”

Section: Discussionmentioning

confidence: 95%

A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3

Chen

et al. 2004

Journal of Biological Chemistry

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“…The following primers were used: msp7ClaI5Ј, GCGATCGATACAC-CAGTAAATAATGAAGAAGAT; msp7PstI3Ј, GCGCTGCAGTTAC-ATTGTGTTTTAGTAAATTAA-ATG; msp6ClaI5Ј, GCGATCGAT-GAAAATAACTTTATCAGAAA-TGAAC; msp6XbaI3Ј, GCGTCTAGATTAATTATTACTA-AATAGATGGAT; and msp6p36ClaI5Ј, GCGCATCGATA-TCGAAGGTCGTTCTGAAACAAATAA. The unique ClaI cleavage sites generated at the 5Ј end of the two genes allowed their cloning downstream of a glutathione S-transferase (GST) 3 or His 6 encoding sequence within appropriately modified pZ expression vectors (22). The DNAs cloned were verified by sequence analysis.…”

Section: Methodsmentioning

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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“…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

105

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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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The merozoite surface protein 6 gene codes for a 36 kDa protein associated with the Plasmodium falciparum merozoite surface protein-1 complex

Cited by 111 publications

References 54 publications

A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3

A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3

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

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

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