The Toxoplasma Micronemal Protein MIC4 Is an Adhesin Composed of Six Conserved Apple Domains

Brecht, Susan; Carruthers, Vern B.; Ferguson, David J. P.; Giddings, Olivia K.; Wang, George; Jäkle, Ursula; Harper, Jill M.; Sibley, L. David; Soldati, Dominique

doi:10.1074/jbc.m008294200

Cited by 137 publications

(132 citation statements)

References 39 publications

(48 reference statements)

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“…Similarly, T. gondii MIC-4 apple domains have distinct functions. The sixth apple domain interacts with host cells, whereas the first two apple domains are required for microneme targeting (52,53). The number of studies in which PAN domain interactions have been examined at a molecular level is limited, but the manner by which PAN domains interact with their ligands does not appear to be conserved.…”

Section: Ama1 Domains I؉ii Consists Of Two Tandem Pan Domainsmentioning

confidence: 99%

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Bai

Becker

Gupta

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

190

272

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Apical membrane antigen 1 (AMA1) is a leading malaria vaccine candidate that possesses polymorphisms that may pose a problem for a vaccine based on this antigen. Knowledge of the distribution of the polymorphic sites on the surface of AMA1 is necessary to obtain a detailed understanding of their significance for vaccine development. For this reason we have sought to determine the three-dimensional structure of AMA1 using x-ray crystallography. The central two-thirds of AMA1 is relatively conserved among Plasmodium species as well as more distantly related apicomplexan parasites, and contains two clusters of disulfide-bonded cysteines termed domains I and II. The crystal structure of this fragment of AMA1 reported here reveals that domains I؉II consists of two intimately associated PAN domains. PAN domain I contains many long loops that extend from the domain core and form a scaffold for numerous polymorphic residues. This extreme adaptation of a PAN domain reveals how malaria parasites have introduced significant flexibility and variation into AMA1 to evade protective human antibody responses. The polymorphisms on the AMA1 surface are exclusively located on one side of the molecule, presumably because this region of AMA1 is most accessible to antibodies reacting with the parasite surface. Moreover, the most highly polymorphic residues surround a conserved hydrophobic trough that is ringed by domain I and domain II loops. Precedents set by viral receptor proteins would suggest that this is likely to be the AMA1 receptor binding pocket.

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Section: Ama1 Domains I؉ii Consists Of Two Tandem Pan Domainsmentioning

confidence: 99%

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Bai

Becker

Gupta

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

190

272

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“…Among these microneme proteins, the members of the thrombospondinrelated anonymous protein (TRAP) family, including TgMIC2 in T. gondii, are known to play an essential role in host cell invasion (Sultan et al, 1997;Yuda et al, 1999;Templeton et al, 2000;Huynh et al, 2003). In T. gondii, microneme proteins form complexes, such as TgMIC1/ MIC4/MIC6, TgMIC3/MIC8 and TgMIC2/M2AP Carruthers, 2002;Dowse and Soldati, 2004), which are composed of a transmembrane escorter protein (TgMIC6, TgMIC8 or TgMIC2) essential for the correct targeting of the complex to the micronemes, and soluble proteins, some of which exhibit host cell binding properties (TgMIC1, TgMIC4 and TgMIC3) (Fourmaux et al, 1996;Garcia-Reguet et al, 2000;Brecht et al, 2001). After discharge by the micronemes, TgMIC2 is processed by two proteolytic activities named microneme protein protease 1 and 2 (MPP1 and MPP2, respectively) .…”

Section: Introductionmentioning

confidence: 99%

Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

Dowse

Pascall

Brown

et al. 2005

International Journal for Parasitology

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112

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Apicomplexan parasites secrete transmembrane (TM) adhesive proteins as part of the process leading to host cell attachment and invasion. These microneme proteins are cleaved in their TM domains by an unidentified protease termed microneme protein protease 1 (MPP1). The cleavage site sequence (IAYGG), mapped in the Toxoplasma gondii microneme proteins TgMIC2 and TgMIC6, is conserved in microneme proteins of other apicomplexans including Plasmodium species. We report here the characterisation of novel T. gondii proteins belonging to the rhomboid family of intramembrane-cleaving serine proteases. T. gondii possesses six genes encoding rhomboid-like proteins. Four are localised along the secretory pathway and therefore constitute possible candidates for MPP1 activity. Toxoplasma rhomboids TgROM1, TgROM2 and TgROM5 cleave the TM domain of Drosophila Spitz, an established substrate for rhomboids from several species, demonstrating that they are active proteases. In addition, TgROM2 cleaves chimeric proteins that contain the TM domains of TgMIC2 and TgMIC12. q

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“…1B) whereas capping is observed for apical invasion proteins. Shaving occurs continuously as the parasite penetrates and is (Dubremetz et al ., 1985;Grimwood and Smith, 1995) Yes (Mineo and Kasper, 1994;He et al ., 2002) Unknown TgMIC1/MIC4/MIC6 (Meissner et al ., 2002b) Yes (Fourmaux et al ., 1996;Brecht et al ., 2001) MPP1 TgMIC2/M2AP Yes (Carruthers et al ., 1999;Harper et al ., 2004) MPP1 Zhou et al ., 2004) TgMIC3/MIC8 (Meissner et al ., 2002b) Yes (Garcia-Reguet et al ., 2000;Meissner et al ., 2002b) MPP1 TgAMA1 (Donahue et al ., 2000;Hehl et al ., 2000) Unknown MPP1 (S. A. Howell, M. J. Blackman and V. B. Carruthers, unpublished) Plasmodium PfTRAP and PbTRAP (Bhanot et al, 2003;Silvie et al ., 2004) Yes (McCormick et al ., 1999;Akhouri et al ., 2004) Serine protease (Silvie et al .. 2004) PfCSP (Stewart and Vanderberg, 1988; Yes (Pinzon-Ortiz et al ., 2001) Unknown PfMSP1/MSP6/MSP7 (Stafford et al ., 1994) Yes (Goel et al ., 2003;Li et al ., 2004) MESH (Howell et al ., 2003) PkAMA1 and PfAMA1 (Deans et al ., 1984;Howell et al ., 2001) Yes (Fraser et al ., 2001) MESH (Howell et al ., 2003) EBL-DBP (Camus and Hadley, 1985;Haynes et al ., 1988) Yes (Camus and Hadley, 1985;Haynes et al ., 1988) Unknown Py235 (Ogun and Holder, 1996) Yes (Ogun and Holde...…”

Section: Primed For Penetrationmentioning

confidence: 99%

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

Carruthers

Blackman²

2005

Molecular Microbiology

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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 Toxoplasma Micronemal Protein MIC4 Is an Adhesin Composed of Six Conserved Apple Domains

Cited by 137 publications

References 39 publications

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

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

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