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.
Human hookworm infection is a major cause of anemia and malnutrition of adults and children in the developing world. As part of on-going efforts to control hookworm infection, The Human Hookworm Vaccine Initiative has identified candidate vaccine antigens from the infective L3 larval stages of the parasite, including a family of pathogenesis-related (PR) proteins known as the Ancylostoma-secreted proteins (ASPs). A novel crystal structure of Na-ASP-2, a PR-1 protein secreted by infective larvae of the human hookworm Necator americanus, has been solved to resolution limits of 1.68 A and to an R-factor of 17% using the recombinant protein expressed in and secreted by Pichia pastoris. The overall fold of Na-ASP-2 is a three-layer alphabetaalpha sandwich flanked by an N-terminal loop and a short, cysteine-rich C terminus. Our structure reveals a large central cavity that is flanked by His129 and Glu106, two residues that are well conserved in all parasitic nematode L3 ASPs. Na-ASP-2 has structural and charge similarities to chemokines, which suggests that Na-ASP-2 may be an extra-cellular ligand of an unknown receptor. Na-ASP-2 is a useful homology model for NIF, a natural antagonistic ligand of CR3 receptor. From these modeling studies, possible binding modes were predicted. In addition, this first structure of a PR-1 protein from parasitic helminths may shed light on the molecular basis of host-parasite interactions.
Asojo
Oluwatoyin A
OA
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, Omaha, NE 68198-7696, USA. oasojo@unmc.edu
Goud
Gaddam
G
Dhar
Kajari
K
Loukas
Alex
A
Zhan
Bin
B
Deumic
Vehid
V
Liu
Sen
S
Borgstahl
Gloria E O
GE
Hotez
Peter J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D000947:Antigens, Helminth / Q000737:chemistry / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002630:Chemotactic Factors / Q000737:chemistry; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D018509:DNA, Helminth / Q000235:genetics; D015801:Helminth Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D008970:Molecular Weight; D017221:Necator americanus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D009332:Necatoriasis / Q000276:immunology / Q000517:prevention & control*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D014612:Vaccines / Q000737:chemistry / Q000235:genetics
D000947:Antigens, Helminth; D002630:Chemotactic Factors; D018509:DNA, Helminth; D015801:Helminth Proteins; D008024:Ligands; D016177:Macrophage-1 Antigen; D014612:Vaccines; D010447:Peptide Hydrolases