Multimerization of the Toxoplasma gondii MIC2 integrin-like A-domain is required for binding to heparin and human cells

Harper, Jill M.; Hoff, Eleanor F; Carruthers, Vern B.

doi:10.1016/j.molbiopara.2003.12.001

Cited by 50 publications

(57 citation statements)

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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MPP1 TgAMA1 (Donahue et al ., 2000;Hehl et al ., 2000) Unknown MPP1 (S. A. Howell, M. J. Blackman and V. B. Carruthers, unpublished) Plasmodium PfTRAP and PbTRAP (Bhanot et al, 2003;Silvie et al ., 2004) Yes (McCormick et al ., 1999;Akhouri et al ., 2004) Serine protease (Silvie et al ..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%

“…One could imagine that a mechanism that clipped such an adhesin from the invader's membrane would effectively reverse binding. TgMIC2/M2AP derived from parasite lysates binds to host cells in a multimeric form, but does not bind at all in its shed form (Carruthers et al, 1999;Harper et al, 2004) and this could be a result of either or both of the above mechanisms. One can conceive certain evolutionary advantages in mechanisms that remove adhesins from the parasite surface while simultaneously decreasing their affinity/avidity for their host cell receptor, as invaded cells might otherwise remain 'marked' by surface-bound parasite antigens which could target them for recognition and destruction by complement or cell-mediated effector immune responses.…”

Section: Give It Up and Let It Gomentioning

confidence: 99%

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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%

Section: Give It Up and Let It Gomentioning

confidence: 99%

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

Carruthers

Blackman²

2005

Molecular Microbiology

104

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Section: Introductionmentioning

confidence: 99%

“…As a member of the phylum Apicomplexa, T. gondii features a distinct apical complex consisting of three types of secretory organelles. Regulated secretion of proteins from the apical micronemes is required for host cell invasion by providing adhesive protein complexes that bind receptors on the host cell surface (Fourmaux et al, 1996;Cerede et al, 2002;Harper et al, 2004a).Similar to regulated secretory proteins in eukaryotes and in other apicomplexan parasites, several Toxoplasma adhesive protein complexes undergo proteolytic maturation while trafficking to the micronemes (Rabenau et al, 2001;Cerede et al, 2002;Binder and Kim, 2004;Dowse and Soldati, 2004). Although more than one-half of the known microneme proteins are processed by removal of an Nterminal or internal propeptide, little is known about the functions of these transient elements in the Apicomplexa (Brydges et al, 2000;Donahue et al, 2000;Cerede et al, 2001;Miller et al, 2001;Rabenau et al, 2001;Reiss et al, 2001;Harper et al, 2004b showed that the propeptide of TgMIC3 plays a regulatory role in masking lectin activity (Cerede et al, 2002), additional functions for protein maturation remain untested.…”

mentioning

confidence: 99%

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

Harper

Huynh

Coppens

et al. 2006

MBoC

101

150

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Propeptides regulate protein function and trafficking in many eukaryotic systems and have emerged as important features of regulated secretory proteins in parasites of the phylum Apicomplexa. Regulated protein secretion from micronemes and host cell invasion are inextricably linked and essential processes for the apicomplexan parasite Toxoplasma gondii. TgM2AP is a propeptide-containing microneme protein found in a heterohexameric complex with the microneme protein TgMIC2, a protein that has a demonstrated fundamental role in gliding motility and invasion. TgM2AP function is also central to these processes, because disruption of TgM2AP (m2apKO) results in secretory retention of TgMIC2, leading to reduced TgMIC2 secretion from the micronemes and impaired invasion. Because the TgM2AP propeptide is predicted to be processed in an intracellular site near where TgMIC2 is retained in m2apKO parasites, we hypothesized that the propeptide and its proteolytic removal influence trafficking and secretion of the complex. We found that proTgM2AP traffics through endosomal compartments and that deletion of the propeptide leads to defective trafficking of the complex within or near this site, resulting in aberrant processing and decreased secretion of TgMIC2, impaired invasion, and reduced virulence in vivo, mirroring the phenotypes observed in m2apKO parasites. In contrast, mutation of several cleavage site residues resulted in normal localization, but it affected the stability and secretion of the complex from the micronemes. Therefore, the propeptide and its cleavage site influence distinct aspects of TgMIC2-M2AP function, with both impacting the outcome of infection. INTRODUCTIONEukaryotic secretory proteins use an assortment of luminal or cytoplasmic forward targeting signals to navigate the secretory system for eventual delivery to the extracellular environment. Among the least well understood of the luminal signals are cleavable elements known as propeptides, which are typically positioned either internally or, more commonly, at the N terminus of a protein. Propeptides have been shown to serve in several capacities. They can facilitate the folding of their cognate protein, regulate its activity or oligomeric assembly, or direct it to a particular intracellular compartment within the endolysosomal or secretory system. For proproteins destined for the regulated secretory pathway, proteolytic processing (also termed proteolytic maturation) typically accompanies the condensation of immature secretory granule contents (Orci et al., 1987;Kuiper and Martens, 2000). Yet, the precise role of proteolytic maturation in the biogenesis and discharge of regulated secretory organelles remains contentious (Arvan and Halban, 2004).Toxoplasma gondii, the etiological agent of toxoplasmosis, is a genetically tractable protozoan parasite that causes widespread infection in humans resulting in significant economic losses worldwide (Jones et al., 2001). As a member of the phylum Apicomplexa, T. gondii features a distinct apical complex consis...

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“…[81] Toxoplasma gondii, Plasmodium Structures of the human thrombospondin-1 type 1 repeats (PDB accession code 1lsl) and the TSR domain of a Plasmodium TRAP (2bbx) are known. [82][83][84][85] Ancylostoma ceylanicum Ace-MIF Cytokine ortholog CD74 The macrophage migration inhibiting factor (MIF) acts as a lymphocyte chemo-attractant, similar to the human orthologue and possesses tautomerase activity. Vaccination provided partial protection from disease.…”

Section: Secreted Integrin Antagonist With Rgd Motif Plant Integrinlimentioning

confidence: 99%

The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

et al. 2014

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1Mason et al. Structures of parasite proteinsNew interventions against infectious diseases require a detailed knowledge and understanding of pathogen-host interactions and pathogeneses at the molecular level. The combination of the considerable advances in systems biology research with methods to explore the structural biology of molecules is poised to provide new insights into these areas. Importantly, exploring threedimensional structures of proteins is central to understanding disease processes, and establishing structure-function relationships assists in identification and assessment of new drug and vaccine targets. Frequently, the molecular arsenal deployed by invading pathogens, and in particular parasites, reveals a common theme whereby families of proteins with conserved three-dimensional folds play crucial roles in infectious processes, but individual members of such families show high levels of specialisation which is often achieved through grafting particular structural features onto the shared overall fold. Accordingly, the applicability of predictive methodologies based on the primary structure of proteins or genome annotations is limited, particularly when thorough knowledge of molecular level mechanisms is required. Such instances exemplify the need for experimental threedimensional structures provided by protein crystallography, which remain an essential component of this area of research. In the present article, we review two examples of key protein families recently investigated in our laboratories, which could represent intervention targets in the metabolome or secretome of parasites. IntroductionInfectious diseases caused by eukaryotic pathogens represent a major disease burden to humans world-wide. In the absence of effective preventative approaches and new intervention strategies, this burden is likely to increase further, [1,2] compounded by food and water shortages, economic crises, wars and climate change, particularly in disadvantaged countries. In addition, there is evidence of increasing problems with resistance in pathogens against a broad range of chemotherapeutic agents, compromising the treatment of infectious diseases. [3] Moreover, in spite of major efforts, there are very few examples of success in developing new drugs and vaccines against eukaryotic pathogens, [4,5] indicating that alternative methods are needed at a time of major advances in molecular and computer technologies. In our opinion, the development of new treatments requires a detailed understanding of pathogens, host interactions and the molecular processes of disease. For instance, knowledge of the three-dimensional structures of proteins with pivotal roles in disease, and the probing of their underlying biology are crucial for understanding the pathogenesis. Through establishing the relevant structure-function relationships, one can elucidate how individual proteins function, so that new ways of disrupting relevant pathways can be found, in order to facilitate the identification of new drug and vaccine targets. ...

show abstract

Multimerization of the Toxoplasma gondii MIC2 integrin-like A-domain is required for binding to heparin and human cells

Cited by 50 publications

References 50 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

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

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