title: Ancylostoma ceylanicum excretory-secretory protein 2 adopts a netrin-like fold and defines a novel family of nematode proteins.
abstract: Hookworms are human parasites that have devastating effects on global health, particularly in underdeveloped countries. Ancylostoma ceylanicum infects humans and animals, making it a useful model organism to study disease pathogenesis. A. ceylanicum excretory-secretory protein 2 (AceES-2), a highly immunoreactive molecule secreted by adult worms at the site of intestinal attachment, is partially protective when administered as a mucosal vaccine against hookworm anemia. The crystal structure of AceES-2 determined at 1.75 Å resolution shows that it adopts a netrin-like fold similar to that found in tissue inhibitors of matrix metalloproteases (TIMPs) and in complement factors C3 and C5. However, recombinant AceES-2 does not significantly inhibit the 10 most abundant human matrix metalloproteases or complement-mediated cell lysis. The presence of a highly acidic surface on AceES-2 suggests that it may function as a cytokine decoy receptor. Several small nematode proteins that have been annotated as TIMPs or netrin-domain-containing proteins display sequence homology in structurally important regions of AceES-2's netrin-like fold. Together, our results suggest that AceES-2 defines a novel family of nematode netrin-like proteins, which may function to modulate the host immune response to hookworm and other parasites.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA.
authors.forename: Kaury
authors.initials: K
authors.lastname: Kucera
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Harrison
authors.forename: Michael
authors.initials: M
authors.lastname: Cappello
authors.forename: Yorgo
authors.initials: Y
authors.lastname: Modis
mesh_terms: D000595:Amino Acid Sequence; D000722:Ancylostoma / Q000276:immunology; D000723:Ancylostomatoidea; D000724:Ancylostomiasis / Q000276:immunology* / Q000469:parasitology; D000818:Animals; D003165:Complement System Proteins / Q000378:metabolism; D015801:Helminth Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000737:chemistry*; D000075388:Netrin-1; D011487:Protein Conformation; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry*
chemical_list: D015801:Helminth Proteins; D009414:Nerve Growth Factors; D019714:Tissue Inhibitor of Metalloproteinases; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D003165:Complement System Proteins; D020782:Matrix Metalloproteinases