TY - JOUR
T1 - 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
AU - Asojo, Oluwatoyin A.
AU - Goud, Gaddam
AU - Dhar, Kajari
AU - Loukas, Alex
AU - Zhan, Bin
AU - Deumic, Vehid
AU - Liu, Sen
AU - Borgstahl, Gloria E.O.
AU - Hotez, Peter J.
N1 - Funding Information:
We thank Dr Youngchool Choe and Dr Charles S. Craik, at the University of California San Francisco, for screening Na-ASP-2 for proteolytic activity against an extensive peptide library. We thank Mr Gilson Baia, Mr Oluwatosin Louis A. Asojo, Ms Abigail Henderson, Dr Nicole La-Rhonde-LeBlanc and Dr Istvan Botos for their support, useful discussion, assistance and encouragement. This research was supported, in part, by the Nebraska Tobacco Settlement Biomedical Research Development Fund (GEOB), which funds the X-ray facility. The Human Hookworm Vaccine Initiative is supported by a grant from The Bill and Melinda Gates Foundation awarded to the Sabin Vaccine Institute and George Washington University Medical Center.
PY - 2005/2/25
Y1 - 2005/2/25
N2 - 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 Å 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 αβα 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.
AB - 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 Å 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 αβα 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.
KW - ASP
KW - Crystal structure
KW - Hookworm
KW - Necator americanus
KW - Pathogenesis-related protein
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U2 - 10.1016/j.jmb.2004.12.023
DO - 10.1016/j.jmb.2004.12.023
M3 - Article
C2 - 15713464
AN - SCOPUS:13844275516
VL - 346
SP - 801
EP - 814
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 3
ER -