Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

Mason, Lyndel, Tribolet, Leon, Simon, Anne, von Gnielinski, Natascha, Nienaber, Lisa, Taylor, Paul, Willis, Charlene, Jones, Malcolm K., Sternberg, Paul W., Gasser, Robin B., Loukas, Alex, and Hofmann, Andreas (2014) Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2. International Journal of Biochemistry and Cell Biology , 50. pp. 146-155.

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Hookworm activation-associated secreted proteins can be structurally classified into at least three different groups. The hallmark feature of Group 1 activation-associated secreted proteins is a prominent equatorial groove, which is inferred to form a ligand binding site. Furthermore, a conserved tandem histidine motif is located in the centre of the groove and believed to provide or support a yet to be determined catalytic activity.

Here, we report three-dimensional crystal structures of Na-ASP-2, an L3-secreted activation-associated secreted protein from the human hookworm Necator americanus, which demonstrate transition metal binding ability of the conserved tandem histidine motif. We further identified moderate phosphohydrolase activity of recombinant Na-ASP-2, which relates to the tandem histidine motif. By panning a random 12-mer peptide phage library, we identified a peptide with high similarity to the human calcium-activated potassium channel SK3, and confirm binding of the synthetic peptide to recombinant Na-ASP-2 by differential scanning fluorimetry. Potential binding modes of the peptide to Na-ASP-2 were studied by molecular dynamics simulations which clearly identify a preferred topology of the Na-ASP-2:SK3 peptide complex.

Item ID: 33115
Item Type: Article (Research - C1)
ISSN: 1878-5875
Additional Information:

activation-associated secreted proteins; host–parasite interactions; pathogenesis-related proteins; protein structure; SCP/TAPS proteins

Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC LP100100092
Date Deposited: 03 Jun 2014 05:52
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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