- Oluwatoyin A. Asojo (4)
- Rabih Darwiche (3)
- Claire Drurey (3)
- Selam Gebremedhin (1)
- Ruud H.P. Wilbers (2)
- M.H.M. Holterman (1)
- Jose L. Lozano-Torres (1)
- J.L. Lozano Torres (1)
- Fernanda Lugo (1)
- Rick M. Maizels (3)
- Jeroen Pollet (1)
- Roger Schneiter (3)
- G. Smant (2)
- Geert Smant (2)
- K. Varossieau (1)
- Koen Varossieau (1)
- R.H.P. Wilbers (2)
Secreted venom allergen-like proteins of helminths: Conserved modulators of host responses in animals and plants
Wilbers, R.H.P. ; Schneiter, Roger ; Holterman, M.H.M. ; Drurey, Claire ; Smant, G. ; Asojo, Oluwatoyin A. ; Maizels, Rick M. ; Lozano Torres, J.L. - \ 2018
PLoS Pathogens 14 (2018)10. - ISSN 1553-7366
Despite causing considerable damage to host tissue at the onset of parasitism, invasive helminths establish remarkably persistent infections in both animals and plants. Secretions released by these obligate parasites during host invasion are thought to be crucial for their persistence in infection. Helminth secretions are complex mixtures of molecules, most of which have unknown molecular targets and functions in host cells or tissues. Although the habitats of animal- and plant-parasitic helminths are very distinct, their secretions share the presence of a structurally conserved group of proteins called venom allergen-like proteins (VALs). Helminths abundantly secrete VALs during several stages of parasitism while inflicting extensive damage to host tissue. The tight association between the secretion of VALs and the onset of parasitism has triggered a particular interest in this group of proteins, as improved knowledge on their biological functions may assist in designing novel protection strategies against parasites in humans, livestock, and important food crops.
|Plant-based production of a vaccine candidate against human filariasis
Varossieau, K. ; Wilbers, R.H.P. ; Asojo, Oluwatoyin A. ; Darwiche, Rabih ; Smant, G. - \ 2018
Crystal structure of Brugia malayi venom allergen-like protein-1 (BmVAL-1), a vaccine candidate for lymphatic filariasis
Darwiche, Rabih ; Lugo, Fernanda ; Drurey, Claire ; Varossieau, Koen ; Smant, Geert ; Wilbers, Ruud H.P. ; Maizels, Rick M. ; Schneiter, Roger ; Asojo, Oluwatoyin A. - \ 2018
International Journal for Parasitology 48 (2018)5. - ISSN 0020-7519 - p. 371 - 378.
Brugia malayi is a causative agent of lymphatic filariasis, a major tropical disease. The infective L3 parasite stage releases immunomodulatory proteins including the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (Sperm-coating protein/Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. BmVAL-1 is a major target of host immunity with >90% of infected B. malayi microfilaraemic cases being seropositive for antibodies to BmVAL-1. This study is part of ongoing efforts to characterize the structures and functions of important B. malayi proteins. Recombinant BmVAL-1 was produced using a plant expression system, crystallized and the structure was solved by molecular replacement and refined to 2.1 Å, revealing the characteristic alpha/beta/alpha sandwich topology of eukaryotic SCP/TAPS proteins. The protein has more than 45% loop regions and these flexible loops connect the helices and strands, which are longer than predicted based on other parasite SCP/TAPS protein structures. The large central cavity of BmVAL-1 is a prototypical CRISP cavity with two histidines required to bind divalent cations. The caveolin-binding motif (CBM) that mediates sterol binding in SCP/TAPS proteins is large and open in BmVAL-1 and is N-glycosylated. N-glycosylation of the CBM does not affect the ability of BmVAL-1 to bind sterol in vitro. BmVAL-1 complements the in vivo sterol export phenotype of yeast mutants lacking their endogenous SCP/TAPS proteins. The in vitro sterol-binding affinity of BmVAL-1 is comparable with Pry1, a yeast sterol transporting SCP/TAPS protein. Sterol binding of BmVAL-1 is dependent on divalent cations. BmVAL-1 also has a large open palmitate-binding cavity, which binds palmitate comparably to tablysin-15, a lipid-binding SCP/TAPS protein. The central cavity, CBM and palmitatebinding cavity of BmVAL-1 are interconnected within the monomer with channels that can serve as pathways for water molecules, cations and small molecules.
Heligmosomoides polygyrus Venom Allergen-like Protein-4 (HpVAL-4) is a sterol binding protein
Asojo, Oluwatoyin A. ; Darwiche, Rabih ; Gebremedhin, Selam ; Smant, Geert ; Lozano-Torres, Jose L. ; Drurey, Claire ; Pollet, Jeroen ; Maizels, Rick M. ; Schneiter, Roger ; Wilbers, Ruud H.P. - \ 2018
International Journal for Parasitology 48 (2018)5. - ISSN 0020-7519 - p. 359 - 369.
Heligmosomoides polygyrus bakeri is a model parasitic hookworm used to study animal and human helminth diseases. During infection, the parasite releases excretory/secretory products that modulate the immune system of the host. The most abundant protein family in excretory/secretory products comprises the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (sperm-coating protein/ Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. There are >30 secreted Heligmosomoides polygyrus VAL proteins (HpVALs) and these proteins are characterised by having either one or two 15 kDa CAP (cysteine-rich secretory protein (CRISP)/antigen 5/pathogenesis related-1) domains. The first known HpVAL structure, HpVAL-4, refined to 1.9 Å is reported. HpVAL-4 was produced as a homogeneously glycosylated protein in leaves of Nicotiana benthamiana infiltrated with recombinant plasmids, making this plant expression platform amenable for the production of biological products. The overall topology of HpVAL-4 is a three layered aba sandwich between a short N-terminal loop and a C-terminal cysteine rich extension. The C-terminal cysteine rich extension has two strands stabilized by two disulfide bonds and superposes well with the previously reported extension from the human hookworm Necator americanus Ancylostoma secreted protein-2 (Na-ASP-2). The N-terminal loop is connected to alpha helix 2 via a disulfide bond previously observed in Na-ASP-2. HpVAL-4 has a central cavity that is more similar to the Nterminal CAP domain of the two CAP Na-ASP-1 from Necator americanus. Unlike Na-ASP-2, mammalian CRISP, and the C-terminal CAP domain of Na-ASP-1, the large central cavity of HpVAL-4 lacks the two histidines required to coordinate divalent cations. HpVAL-4 has both palmitate-binding and sterol-binding cavities and is able to complement the in vivo sterol export phenotype of yeast mutants lacking their endogenous CAP proteins. More studies are required to determine endogenous binding partners of HpVAL-4 and unravel the possible impact of sterol binding on immune-modulatory functions.