VAL (Venom Allergen-Like) Proteins from Helminths

  • A large multi-gene family in all animal organisms, distant relatives in fungi too, with members placed in overlapping InterPro families 001283, 002413, 014044,014258, 029410, 034113, 034117, 034121, 035940, 047832 and 047899.
  • Predominantly at interfaces eg sperm coating, vector saliva, insect venoms…
  • Synonyms : SCP (Sperm-Coat Protein), ASP (Ancylostoma Secreted Protein), CRISP (Cysteine-Rich Secreted Protein), PRP (Pathogenesis-Related Protein) and TAPS (Tpx-1/Ag5/PR-1/Sc7)
  • Includes Human glioma pathogenesis-related protein (GliPR), mammalian testis-specific protein (Tpx), vespid wasp allergen 5 (Ag5), fire ant venom allergen 3, some snake venoms, lizard helothermine, plant pathogensis (PR-1) proteins, and fungal Sc7 and Sc14 from Schizophyllum commune.
  • Archetypal domain typically of 150 aa with 3 disulphide bonds; most often one- or two-domain proteins, can be found fused to other modules (eg ShK)
  • Expanded in most helminth parasite genomes, often most abundant secreted proteins, some very polymorphic, upregulated in parasitic stages relative to free-living.
  • Prominent vaccine antigens inducing high levels of immunity
  • Many VAL/CAP proteins bind lipids such as sterols and can rescue yeast mutants; venoms in this superfamily commonly block ion channels
  • No other unifying functional attributes, may provide framework for diversification of sequence and function
Detailed reviews of the gene family within helminths published by Wilbers et al (2008) and Cantacessi et al (2009). Reviews on the broader multigene family by Gibbs et al (2008) and Zhang et al (2022).
A schematic of some helminth family members is shown below, this is also available to download as PDF.

Asojo, O.A., Darwiche, R., Gebremedhin, S., Smant, G., Lozano-Torres, J.L., Drurey, C., Pollet, J., Maizels, R.M., Schneiter, R. and Wilbers, R.H.P. (2018). Heligmosomoides polygyrus Venom Allergen-like Protein-4 (HpVAL-4) is a sterol binding protein. Int J Parasitol 48: 359-369.  PMC5893428   10.1016/j.ijpara.2018.01.002. https://www.ncbi.nlm.nih.gov/pubmed/29505764

Asojo, O.A., Goud, G.N., Dhar, K., Loukas, A., Zhan, B., Deumic, V., Liu, A., Borgstahl, G.E.O. and Hotez, P.J. (2005). X-ray structure of Na-ASP-2, a pathogenesis related-1 protein from the nematode parasite, Necator americanus, and a vaccine antigen for human hookworm infection. J Mol Biol 346: 801-814. 

Borloo, J., Geldhof, P., Peelaers, I., Van Meulder, F., Ameloot, P., Callewaert, N., Vercruysse, J., Claerebout, E., Strelkov, S.V. and Weeks, S.D. (2013). Structure of Ostertagia ostertagi ASP-1: insights into disulfide-mediated cyclization and dimerization. Acta Crystallogr D Biol Crystallogr 69(Pt 4): 493-503.    10.1107/S0907444912050019.  http://www.ncbi.nlm.nih.gov/pubmed/23519657

Cantacessi, C., Campbell, B.E., Visser, A., Geldhof, P., Nolan, M.J., Nisbet, A.J., Matthews, J.B., Loukas, A., Hofmann, A., Otranto, D., Sternberg, P.W. and Gasser, R.B. (2009). A portrait of the “SCP/TAPS” proteins of eukaryotes – Developing a framework for fundamental research and biotechnological outcomes. Biotechnol Adv27: 376-388.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19239923

Darwiche, R., Lugo, F., Drurey, C., Varossieau, K., Smant, G., Wilbers, R.H.P., Maizels, R.M., Schneiter, R. and Asojo, O.A. (2018). Crystal structure of Brugia malayi venom allergen-like protein-1 (BmVAL-1), a vaccine candidate for lymphatic filariasis. Int J Parasitol 5: 371-378.  PMC5893361   10.1016/j.ijpara.2017.12.003. https://www.ncbi.nlm.nih.gov/pubmed/29501266

Ding, X., Shields, J., Allen, R. and Hussey, R.S. (2000). Molecular cloning and characterisation of a venom allergen AG5-like cDNA from Meloidogyne incognita. Int J Parasitol 30: 77-81. 

Farias, L.P., Chalmers, I.W., Perally, S., Rofatto, H.K., Jackson, C.J., Brown, M., Khouri, M.I., Barbosa, M.M.F., Hensbergen, P.J., Hokke, C.H., Leite, L.C.C. and Hoffmann, K.F. (2019). Schistosoma mansoni venom allergen-like proteins: phylogenetic relationships, stage-specific transcription and tissue localization as predictors of immunological cross-reactivity. Int J Parasitol 49(8): 593-599.  PMC6598858   10.1016/j.ijpara.2019.03.003. https://www.ncbi.nlm.nih.gov/pubmed/31136745

Gao, B., Allen, R., Maier, T., Davis, E.L., Baum, T.J. and Hussey, R.S. (2001). Molecular characterisation and expression of two venom allergen-like protein genes in Heterodera glycines. Int J Parasitol 31(14): 1617-1625. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11730789

Geldhof, P., Meyvis, Y., Vercruysse, J. and Claerebout, E. (2008). Vaccine testing of a recombinant activation-associated secreted protein (ASP1) from Ostertagia ostertagi. Parasite Immunol 30(1): 57-60.    PIM1001 [pii]

10.1111/j.1365-3024.2007.01001.x.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18086018

Geldhof, P., Meyvis, Y., Vercruysse, J. and Claerebout, E. (2008). Vaccine testing of a recombinant activation-associated secreted protein (ASP1) from Ostertagia ostertagi. Parasite Immunol 30(1): 57-60.    PIM1001 [pii]

10.1111/j.1365-3024.2007.01001.x.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18086018

Gibbs, G.M., Roelants, K. and O’Bryan, M.K. (2008). The CAP superfamily: cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins–roles in reproduction, cancer, and immune defense. Endocr Rev 29(7): 865-897.    er.2008-0032 [pii]

10.1210/er.2008-0032.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18824526

Han, Z., Xiong, D., Schneiter, R. and Tian, C. (2023). The function of plant PR1 and other members of the CAP protein superfamily in plant-pathogen interactions. Mol Plant Pathol 24(6): 651-668.  PMC10189770  10.1111/mpp.13320.  https://www.ncbi.nlm.nih.gov/pubmed/36932700

Hawdon, J.M., Jones, B.F., Hoffman, D.R. and Hotez , P.J. (1996). Cloning and characterization of Ancylostoma-secreted protein.    A novel protein associated with the transition to parasitism by infective hookworm larvae. Journal of Biological Chemistry 271: 6672-6678. 

Hewitson, J.P., Harcus, Y., Murray, J., van Agtmaal, M., Filbey, K.J., Grainger, J.R., Bridgett, S., Blaxter, M.L., Ashton, P.D., Ashford, D.A., Curwen, R.S., Wilson, R.A., Dowle, A.A. and Maizels, R.M. (2011). Proteomic analysis of secretory products from the model gastrointestinal nematode Heligmosomoides polygyrus  reveals dominance of Venom Allergen-Like (VAL) proteins. Journal of Proteomics 74: 1573-1594. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21722761

Lozano-Torres, J.L., Wilbers, R.H., Warmerdam, S., Finkers-Tomczak, A., Diaz-Granados, A., van Schaik, C.C., Helder, J., Bakker, J., Goverse, A., Schots, A. and Smant, G. (2014). Apoplastic venom allergen-like proteins of cyst nematodes modulate the activation of basal plant innate immunity by cell surface receptors. PLoS Pathog10(12): e1004569.  4263768   10.1371/journal.ppat.1004569.  http://www.ncbi.nlm.nih.gov/pubmed/25500833

Maduzia, L.L., Gumienny, T.L., Zimmerman, C.M., Wang, H., Shetgiri, P., Krishna, S., Roberts, A.F. and Padgett, R.W. (2002). lon-1 regulates Caenorhabditis elegans body size downstream of the dbl-1 TGFβ signaling pathway. Dev Biol 246(2): 418-428.    10.1006/dbio.2002.0662.  https://www.ncbi.nlm.nih.gov/pubmed/12051826

Murray, J., Gregory, W.F., Gomez-Escobar, N., Atmadja, A.K. and Maizels, R.M. (2001). Expression and immune recognition of Brugia malayi VAL-1, a homologue of vespid venom allergens and Ancylostoma secreted proteins. Molecular and Biochemical Parasitology 118: 89 – 96. 

Ravi, V., King, T.P., Andersen, J.F., Nutman, T.B. and Neva, F.A. (2005). Strongyloides stercoralis recombinant NIE antigen shares epitope with recombinant Ves v 5 and Pol a 5 allergens of insects. Am J Trop Med Hyg 72: 549-553.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15891128

Ravi, V., Ramachandran, S., Thompson, R.W., Andersen, J.F. and Neva, F.A. (2002). Characterization of a recombinant immunodiagnostic antigen (NIE) from Strongyloides stercoralis L3-stage larvae. Mol Biochem Parasitol 125: 73-81.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12467975

Wilbers, R.H.P., Schneiter, R., Holterman, M.H.M., Drurey, C., Asojo, O.A., Maizels, R.M. and Lozano-Torres, J.L. (2018). Secreted venom allergen-like proteins of helminths: conserved modulators of host responses in animals and plants. PLOS Pathogens 14: e1007300.  PMC6193718. 

Zhang, Q., Xu, J., Zhou, X. and Liu, Z. (2022). CAP superfamily proteins from venomous animals: Who we are and what to do? Int J Biol Macromol 221: 691-702.    10.1016/j.ijbiomac.2022.09.079. https://www.ncbi.nlm.nih.gov/pubmed/36099994