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Article ; Online: The FAR protein family of parasitic nematodes.

Parks, Sophia C / Nguyen, Susan / Boulanger, Martin J / Dillman, Adler R

2022 Volume 18, Issue 4, Page(s) e1010424

Abstract: Fatty acid-and retinol-binding proteins (FARs) belong to a unique family of excreted/secreted proteins (ESPs) found exclusively in nematodes. Much of our understanding of these proteins, however, is limited to their in vitro binding characteristics ... ...

Abstract	Fatty acid-and retinol-binding proteins (FARs) belong to a unique family of excreted/secreted proteins (ESPs) found exclusively in nematodes. Much of our understanding of these proteins, however, is limited to their in vitro binding characteristics toward various fatty acids and retinol and has provided little insight into their in vivo functions or mechanisms. Recent research, however, has shown that FARs elicit an immunomodulatory role in plant and animal model systems, likely by sequestering lipids involved in immune signaling. This alludes to the intricate relationship between parasitic nematode effectors and their hosts.
MeSH term(s)	Animals ; Fatty Acids/metabolism ; Helminth Proteins/genetics ; Helminth Proteins/metabolism ; Nematoda/genetics ; Nematoda/metabolism ; Retinol-Binding Proteins/genetics ; Retinol-Binding Proteins/metabolism ; Vitamin A/metabolism
Chemical Substances	Fatty Acids ; Helminth Proteins ; Retinol-Binding Proteins ; Vitamin A (11103-57-4)
Language	English
Publishing date	2022-04-21
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010424
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Article ; Online: The shear stress of host cell invasion: exploring the role of biomolecular complexes.

Tonkin, Michelle L / Boulanger, Martin J

PLoS pathogens

2015 Volume 11, Issue 1, Page(s) e1004539

MeSH term(s)	Animals ; Apicomplexa/pathogenicity ; Apicomplexa/physiology ; Endocytosis/physiology ; Host-Parasite Interactions/physiology ; Host-Pathogen Interactions/physiology ; Humans ; Macromolecular Substances/chemistry ; Macromolecular Substances/metabolism ; Protozoan Infections/parasitology ; Shear Strength/physiology ; Stress, Mechanical
Chemical Substances	Macromolecular Substances
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1004539
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Article ; Online: An Extended Surface Loop on Toxoplasma gondii Apical Membrane Antigen 1 (AMA1) Governs Ligand Binding Selectivity.

Parker, Michelle L / Boulanger, Martin J

PloS one

2015 Volume 10, Issue 5, Page(s) e0126206

Abstract: Apicomplexan parasites are the causative agents of globally prevalent diseases including malaria and toxoplasmosis. These obligate intracellular pathogens have evolved a sophisticated host cell invasion strategy that relies on a parasite-host cell ... ...

Abstract	Apicomplexan parasites are the causative agents of globally prevalent diseases including malaria and toxoplasmosis. These obligate intracellular pathogens have evolved a sophisticated host cell invasion strategy that relies on a parasite-host cell junction anchored by interactions between apical membrane antigens (AMAs) on the parasite surface and rhoptry neck 2 (RON2) proteins discharged from the parasite and embedded in the host cell membrane. Key to formation of the AMA1-RON2 complex is displacement of an extended surface loop on AMA1 called the DII loop. While conformational flexibility of the DII loop is required to expose the mature RON2 binding groove, a definitive role of this substructure has not been elucidated. To establish a role of the DII loop in Toxoplasma gondii AMA1, we engineered a form of the protein where the mobile portion of the loop was replaced with a short Gly-Ser linker (TgAMA1ΔDIIloop). Isothermal titration calorimetry measurements with a panel of RON2 peptides revealed an influential role for the DII loop in governing selectivity. Most notably, an Eimeria tenella RON2 (EtRON2) peptide that showed only weak binding to TgAMA1 bound with high affinity to TgAMA1ΔDIIloop. To define the molecular basis for the differential binding, we determined the crystal structure of TgAMA1ΔDIIloop in complex with the EtRON2 peptide. When analyzed in the context of existing AMA1-RON2 structures, spatially distinct anchor points in the AMA1 groove were identified that, when engaged, appear to provide the necessary traction to outcompete the DII loop. Collectively, these data support a model where the AMA1 DII loop serves as a structural gatekeeper to selectively filter out ligands otherwise capable of binding with high affinity in the AMA1 apical groove. These data also highlight the importance of considering the functional implications of the DII loop in the ongoing development of therapeutic intervention strategies targeting the AMA1-RON2 invasion complex.
MeSH term(s)	Amino Acid Sequence ; Antigens, Protozoan/chemistry ; Antigens, Protozoan/genetics ; Antigens, Protozoan/metabolism ; Binding Sites ; Calorimetry ; Cloning, Molecular ; Crystallography, X-Ray ; Eimeria tenella/metabolism ; Hydrogen Bonding ; Ligands ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Peptides/chemistry ; Peptides/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protozoan Proteins/chemistry ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; Sequence Alignment ; Toxoplasma/metabolism
Chemical Substances	AMA1 protein, Toxoplasma gondii ; Antigens, Protozoan ; Ligands ; Peptides ; Protozoan Proteins ; Recombinant Proteins ; rhoptry neck protein 2, Toxoplasma gondii
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0126206
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Article ; Online: Monoclonal antibody 7H2.2 binds the C-terminus of the cancer-oocyte antigen SAS1B through the hydrophilic face of a conserved amphipathic helix corresponding to one of only two regions predicted to be ordered.

Legg, Max S G / Gagnon, Susannah M L / Powell, Cameron J / Boulanger, Martin J / Li, Andra J J / Evans, Stephen V

Acta crystallographica. Section D, Structural biology

2022 Volume 78, Issue Pt 5, Page(s) 623–632

Abstract: The structure of the antigen-binding fragment (Fab) of mouse monoclonal antibody 7H2.2 in complex with a 15-residue fragment from the metalloproteinase sperm acrosomal SLLP1 binding protein (SAS1B), which is a molecular and cellular candidate for both ... ...

Abstract	The structure of the antigen-binding fragment (Fab) of mouse monoclonal antibody 7H2.2 in complex with a 15-residue fragment from the metalloproteinase sperm acrosomal SLLP1 binding protein (SAS1B), which is a molecular and cellular candidate for both cancer therapy and female contraception, has been determined at 2.75 Å resolution by single-crystal X-ray diffraction. Although the crystallization conditions contained the final 148 C-terminal residues of SAS1B, the Fab was observed to crystallize in complex with a 15-residue fragment corresponding to one of only two elements of secondary structure that are predicted to be ordered within the C-terminal region of SAS1B. The antigen forms an amphipathic α-helix that binds the 7H2.2 combining site via hydrophilic residues in an epitope that spans the length of the antigen α-helix, with only two CH-π interactions observed along the edge of the interface between the antibody and antigen. Interestingly, the paratope contains two residues mutated away from the germline (YL32F and YH58R), as well as a ProH96-ThrH97-AspH98-AspH99 insertion within heavy chain CDR3. The intact 7H2.2 antibody exhibits high affinity for the SAS1B antigen, with 1:1 binding and nanomolar affinity for both the SAS1B C-terminal construct used for crystallization (3.38 ± 0.59 nM) and a 15-amino-acid synthetic peptide construct corresponding to the helical antigen observed within the crystal structure (1.60 ± 0.31 nM). The SAS1B-antibody structure provides the first structural insight into any portion of the subdomain architecture of the C-terminal region of the novel cancer-oocyte tumor surface neoantigen SAS1B and provides a basis for the targeted use of SAS1B.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Binding Sites, Antibody ; Crystallography, X-Ray ; Female ; Immunoglobulin Fab Fragments/chemistry ; Mice ; Neoplasms ; Oocytes/metabolism ; Protein Conformation
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin Fab Fragments
Language	English
Publishing date	2022-04-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798322003011
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Article ; Online: Toxoplasma gondii mitochondrial association factor 1b interactome reveals novel binding partners including Ral GTPase accelerating protein α1.

Powell, Cameron J / Jenkins, Meredith L / Hill, Tara B / Blank, Matthew L / Cabo, Leah F / Thompson, Lexie R / Burke, John E / Boyle, Jon P / Boulanger, Martin J

The Journal of biological chemistry

2023 Volume 300, Issue 1, Page(s) 105582

Abstract: The intracellular parasite, Toxoplasma gondii, has developed sophisticated molecular strategies to subvert host processes and promote growth and survival. During infection, T. gondii replicates in a parasitophorous vacuole (PV) and modulates host ... ...

Abstract	The intracellular parasite, Toxoplasma gondii, has developed sophisticated molecular strategies to subvert host processes and promote growth and survival. During infection, T. gondii replicates in a parasitophorous vacuole (PV) and modulates host functions through a network of secreted proteins. Of these, Mitochondrial Association Factor 1b (MAF1b) recruits host mitochondria to the PV, a process that confers an in vivo growth advantage, though the precise mechanisms remain enigmatic. To address this knowledge gap, we mapped the MAF1b interactome in human fibroblasts using a commercial Yeast-2-hybrid (Y2H) screen, which revealed several previously unidentified binding partners including the GAP domain of Ral GTPase Accelerating Protein α1 (RalGAPα1(GAP)). Recombinantly produced MAF1b and RalGAPα1(GAP) formed as a stable binary complex as shown by size exclusion chromatography with a K
MeSH term(s)	Humans ; Binding Sites ; Calorimetry ; Chromatography, Gel ; Fibroblasts/metabolism ; Fibroblasts/parasitology ; GTPase-Activating Proteins/chemistry ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Hydrogen Deuterium Exchange-Mass Spectrometry ; Mitochondria/metabolism ; Mitochondria/parasitology ; Protein Interaction Maps ; Protozoan Proteins/chemistry ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Toxoplasma/chemistry ; Toxoplasma/genetics ; Toxoplasma/metabolism ; Two-Hybrid System Techniques
Chemical Substances	GTPase-Activating Proteins ; Protozoan Proteins ; RALGAPA1 protein, human
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105582
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Article ; Online: Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Yanik, Sean / Venkatesh, Varsha / Parker, Michelle L / Ramaswamy, Raghavendran / Diouf, Ababacar / Sarkar, Deepti / Miura, Kazutoyo / Long, Carole A / Boulanger, Martin J / Srinivasan, Prakash

Nature communications

2023 Volume 14, Issue 1, Page(s) 5879

Abstract: Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection ... ...

Abstract	Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-F
MeSH term(s)	Female ; Animals ; Rats ; Broadly Neutralizing Antibodies ; Ligands ; Cell Membrane ; Antibodies, Neutralizing ; Epitopes
Chemical Substances	Broadly Neutralizing Antibodies ; Ligands ; Antibodies, Neutralizing ; Epitopes
Language	English
Publishing date	2023-09-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41636-5
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Article ; Online: Invasion of

Najm, Rania / Ruivo, Margarida T Grilo / Penarete-Vargas, Diana Marcela / Hamie, Maguy / Mouveaux, Thomas / Gissot, Mathieu / Boulanger, Martin J / El Hajj, Hiba / Lebrun, Maryse

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 5, Page(s) e2219533120

Abstract: Toxoplasmosis is a neglected parasitic disease necessitating public health control. Host cell invasion ... ...

Abstract	Toxoplasmosis is a neglected parasitic disease necessitating public health control. Host cell invasion by
MeSH term(s)	Animals ; Toxoplasma/metabolism ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Persistent Infection ; Toxoplasmosis/metabolism ; Parasites/metabolism ; Vaccination
Chemical Substances	Protozoan Proteins
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2219533120
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Article ; Online: Structural characterization of Treponema pallidum Tp0225 reveals an unexpected leucine-rich repeat architecture.

Ramaswamy, Raghavendran / Houston, Simon / Loveless, Bianca / Cameron, Caroline E / Boulanger, Martin J

Acta crystallographica. Section F, Structural biology communications

2019 Volume 75, Issue Pt 7, Page(s) 489–495

Abstract: The phylogenetically divergent spirochete bacterium Treponema pallidum subsp. pallidum is the causative agent of syphilis. Central to the capacity of T. pallidum to establish infection is the ability of the pathogen to attach to a diversity of host cells. ...

Abstract	The phylogenetically divergent spirochete bacterium Treponema pallidum subsp. pallidum is the causative agent of syphilis. Central to the capacity of T. pallidum to establish infection is the ability of the pathogen to attach to a diversity of host cells. Many pathogenic bacteria employ leucine-rich repeat (LRR) domain-containing proteins to mediate protein-protein interactions, including attachment to host components and establishment of infection. Intriguingly, T. pallidum expresses only one putative LRR domain-containing protein (Tp0225) with an unknown function. In an effort to ascribe a function to Tp0225, a comprehensive phylogenetic analysis was first performed; this investigation revealed that Tp0225 clusters with the pathogenic clade of treponemes. Its crystal structure was then determined to 2.0 Å resolution using Pt SAD phasing, which revealed a noncanonical architecture containing a hexameric LRR core with a discontinuous β-sheet bridged by solvent molecules. Furthermore, a surface-exposed, hydrophobic pocket, which was found in Tp0225 but is largely absent in canonical LRR domains from other pathogenic bacteria, may serve to coordinate a hydrophobic ligand. Overall, this study provides the first structural characterization of the sole LRR domain-containing protein from T. pallidum and offers insight into the unique molecular landscape of this important human pathogen.
MeSH term(s)	Bacterial Proteins/chemistry ; Binding Sites ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; Phylogeny ; Protein Domains ; Protein Structure, Secondary ; Proteins/chemistry ; Treponema pallidum/metabolism
Chemical Substances	Bacterial Proteins ; Proteins ; leucine-rich repeat proteins
Language	English
Publishing date	2019-06-26
Publishing country	United States
Document type	Journal Article
ISSN	2053-230X
ISSN (online)	2053-230X
DOI	10.1107/S2053230X19007726
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Article ; Online: MyosinA is a druggable target in the widespread protozoan parasite Toxoplasma gondii.

Kelsen, Anne / Kent, Robyn S / Snyder, Anne K / Wehri, Eddie / Bishop, Stephen J / Stadler, Rachel V / Powell, Cameron / Martorelli di Genova, Bruno / Rompikuntal, Pramod K / Boulanger, Martin J / Warshaw, David M / Westwood, Nicholas J / Schaletzky, Julia / Ward, Gary E

PLoS biology

2023 Volume 21, Issue 5, Page(s) e3002110

Abstract: Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. The ability of T. gondii and other apicomplexan parasites to invade into, egress from, and move between cells of the hosts they infect is critical ... ...

Abstract	Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. The ability of T. gondii and other apicomplexan parasites to invade into, egress from, and move between cells of the hosts they infect is critical to parasite virulence and disease progression. An unusual and highly conserved parasite myosin motor (TgMyoA) plays a central role in T. gondii motility. The goal of this work was to determine whether the parasite's motility and lytic cycle can be disrupted through pharmacological inhibition of TgMyoA, as an approach to altering disease progression in vivo. To this end, we first sought to identify inhibitors of TgMyoA by screening a collection of 50,000 structurally diverse small molecules for inhibitors of the recombinant motor's actin-activated ATPase activity. The top hit to emerge from the screen, KNX-002, inhibited TgMyoA with little to no effect on any of the vertebrate myosins tested. KNX-002 was also active against parasites, inhibiting parasite motility and growth in culture in a dose-dependent manner. We used chemical mutagenesis, selection in KNX-002, and targeted sequencing to identify a mutation in TgMyoA (T130A) that renders the recombinant motor less sensitive to compound. Compared to wild-type parasites, parasites expressing the T130A mutation showed reduced sensitivity to KNX-002 in motility and growth assays, confirming TgMyoA as a biologically relevant target of KNX-002. Finally, we present evidence that KNX-002 can slow disease progression in mice infected with wild-type parasites, but not parasites expressing the resistance-conferring TgMyoA T130A mutation. Taken together, these data demonstrate the specificity of KNX-002 for TgMyoA, both in vitro and in vivo, and validate TgMyoA as a druggable target in infections with T. gondii. Since TgMyoA is essential for virulence, conserved in apicomplexan parasites, and distinctly different from the myosins found in humans, pharmacological inhibition of MyoA offers a promising new approach to treating the devastating diseases caused by T. gondii and other apicomplexan parasites.
MeSH term(s)	Humans ; Animals ; Mice ; Toxoplasma/genetics ; Parasites ; Myosins ; Mutation ; Protozoan Proteins/genetics
Chemical Substances	Myosins (EC 3.6.4.1) ; Protozoan Proteins
Language	English
Publishing date	2023-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3002110
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Article ; Online: The Trypanosoma brucei MISP family of invariant proteins is co-expressed with BARP as triple helical bundle structures on the surface of salivary gland forms, but is dispensable for parasite development within the tsetse vector.

Casas-Sanchez, Aitor / Ramaswamy, Raghavendran / Perally, Samïrah / Haines, Lee R / Rose, Clair / Aguilera-Flores, Marcela / Portillo, Susana / Verbeelen, Margot / Hussain, Shahid / Smithson, Laura / Yunta, Cristina / Lehane, Michael J / Vaughan, Sue / van den Abbeele, Jan / Almeida, Igor C / Boulanger, Martin J / Acosta-Serrano, Álvaro

PLoS pathogens

2023 Volume 19, Issue 3, Page(s) e1011269

Abstract: Trypanosoma brucei spp. develop into mammalian-infectious metacyclic trypomastigotes inside tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, little is known about the metacyclic expression of invariant surface antigens. ...

Abstract	Trypanosoma brucei spp. develop into mammalian-infectious metacyclic trypomastigotes inside tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, little is known about the metacyclic expression of invariant surface antigens. Proteomic analyses of saliva from T. brucei-infected tsetse flies identified, in addition to VSG and Brucei Alanine-Rich Protein (BARP) peptides, a family of glycosylphosphatidylinositol (GPI)-anchored surface proteins herein named as Metacyclic Invariant Surface Proteins (MISP) because of its predominant expression on the surface of metacyclic trypomastigotes. The MISP family is encoded by five paralog genes with >80% protein identity, which are exclusively expressed by salivary gland stages of the parasite and peak in metacyclic stage, as shown by confocal microscopy and immuno-high resolution scanning electron microscopy. Crystallographic analysis of a MISP isoform (MISP360) and a high confidence model of BARP revealed a triple helical bundle architecture commonly found in other trypanosome surface proteins. Molecular modelling combined with live fluorescent microscopy suggests that MISP N-termini are potentially extended above the metacyclic VSG coat, and thus could be tested as a transmission-blocking vaccine target. However, vaccination with recombinant MISP360 isoform did not protect mice against a T. brucei infectious tsetse bite. Lastly, both CRISPR-Cas9-driven knock out and RNAi knock down of all MISP paralogues suggest they are not essential for parasite development in the tsetse vector. We suggest MISP may be relevant during trypanosome transmission or establishment in the vertebrate's skin.
MeSH term(s)	Animals ; Mice ; Trypanosoma brucei brucei/genetics ; Parasites ; Membrane Proteins ; Alanine ; Proteomics ; Salivary Glands/parasitology ; Trypanosoma ; Mammals ; Membrane Glycoproteins
Chemical Substances	Membrane Proteins ; Alanine (OF5P57N2ZX) ; BARP protein, mouse ; Membrane Glycoproteins
Language	English
Publishing date	2023-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011269
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