Solution structure of an EGF module pair from the Plasmodium falciparum merozoite surface protein 1 1 1Edited by P. E. Wright

Morgan, W. T. J.; Birdsall, B.; Frenkiel, Thomas A.; Gradwell, Michael G.; Burghaus, Petra A.; Syed, Shabih E.-H.; Uthaipibull, Chairat; Holder, Anthony A.; Feeney, J.

doi:10.1006/jmbi.1999.2753

Cited by 142 publications

(129 citation statements)

References 29 publications

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“…MSP-6 36 interacts with p38 via its C terminus (C ). With the exception of the C-terminal p19 (30,31), which is part of p42, there is no detailed structural information available for the various interacting proteins, which are roughly drawn to scale.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…The R-work and R-free are 23.4% and 26.4%, respectively, using all reflections to 2.4 Å. Calculations-Least squares superpositions were performed using the program LSQMAN (41) with a distance cutoff of 3.8 Å, and coordinate transformations were applied using the program MOLEMAN2 (41). Structural comparisons with the NMR structure of P. falciparum MSP-1 19 (28) use the most representative member of the ensemble. Electrostatic calculations include only the native MSP-1 19 sequence, without the secretory signal and purification epitope.…”

Section: Methodsmentioning

confidence: 99%

Structure of the C-terminal Domains of Merozoite Surface Protein-1 from Plasmodium knowlesi Reveals a Novel Histidine Binding Site

Garman¹,

Simcoke²,

Stowers³

et al. 2003

Journal of Biological Chemistry

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The protozoan parasite Plasmodium causes malaria, with hundreds of millions of cases recorded annually. Protection against malaria infection can be conferred by antibodies against merozoite surface protein (MSP)-1, making it an attractive vaccine candidate. Here we present the structure of the C-terminal domains of MSP-1 (known as MSP-1 19 ) from Plasmodium knowlesi. The structure reveals two tightly packed epidermal growth factor-like domains oriented head to tail. In domain 1, the molecule displays a histidine binding site formed primarily by a highly conserved tryptophan. The protein carries a pronounced overall negative charge primarily due to the large number of acidic groups in domain 2. To map protein binding surfaces on MSP-1 19 , we have analyzed the crystal contacts in five different crystal environments, revealing that domain 1 is highly preferred in protein-protein interactions. A comparison of MSP-1 19 structures from P. knowlesi, P. cynomolgi, and P. falciparum shows that, although the overall protein folds are similar, the molecules show significant differences in charge distribution. We propose the histidine binding site in domain 1 as a target for inhibitors of protein binding to MSP-1, which might prevent invasion of the merozoite into red blood cells.

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“…The protease hydrolyses a single Leu-Asn bond just Nterminal to the first cysteine of the MSP-1 19 domain. Although this is some 96 residues upstream of the GPI anchor, the compact, inverted U-shaped structure of the two EGF-like modules which make up MSP-1 19 (Morgan et al, 1999;Pizarro et al, 2003) means that the cleavage site is probably spatially close to the membrane. A recent analysis of shedding of P. falciparum apical membrane antigen-1 (PfAMA1) showed that release from the parasite surface is the result of cleavage at a Thr-Ser bond just 29 residues upstream of the TMD (Howell et al, 2003).…”

Section: It's What You Do Not the Way That You Do Itmentioning

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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Solution structure of an EGF module pair from the Plasmodium falciparum merozoite surface protein 1 1 1Edited by P. E. Wright

Cited by 142 publications

References 29 publications

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

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

Structure of the C-terminal Domains of Merozoite Surface Protein-1 from Plasmodium knowlesi Reveals a Novel Histidine Binding Site

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

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