Structural highlights
Function
[TOT1A_HADVE] Reversibly and voltage-independently blocks both mid-low- (M-LVA) and high-voltage-activated (HVA) calcium channels in cockroach DUM neurons. Lethal to many insect orders but not toxic to mice or rabbits. May target the insect high-voltage-activated calcium channel Dmca1D. Also inhibits acarines calcium channels. An extremely high toxin concentration partially inhibits Cav1.2/CACNA1C, Cav2.1/CACNA1A and Cav2.2/CACNA1B calcium channel of rats. As for omega-AcTx-Hv2a, the phenotypic effect of injection of this toxin into lone star ticks (Amblyomma americanum) is curling of all eight legs into closed loops.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
omega-Atracotoxin-Hv1a is an insect-specific neurotoxin whose phylogenetic specificity derives from its ability to antagonize insect, but not vertebrate, voltage-gated calcium channels. In order to help understand its mechanism of action and to enhance its utility as a lead compound for insecticide development, we used a combination of protein engineering and site-directed mutagenesis to probe the toxin for key functional regions. First, we constructed a Hairpinless mutant in which the C-terminal beta-hairpin, which is highly conserved in this family of neurotoxins, was excised without affecting the fold of the residual disulfide-rich core of the toxin. The Hairpinless mutant was devoid of insecticidal activity, indicating the functional importance of the hairpin. We subsequently developed a highly efficient system for production of recombinant toxin and then probed the hairpin for key functional residues using alanine-scanning mutagenesis followed by a second round of mutagenesis based on initial "hits" from the alanine scan. This revealed that two spatially proximal residues, Asn(27) and Arg(35), form a contiguous molecular surface that is essential for toxin activity. We propose that this surface of the beta-hairpin is a key site for interaction of the toxin with insect calcium channels.
Functional significance of the beta hairpin in the insecticidal neurotoxin omega-atracotoxin-Hv1a.,Tedford HW, Fletcher JI, King GF J Biol Chem. 2001 Jul 13;276(28):26568-76. Epub 2001 Apr 19. PMID:11313356[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bloomquist JR. Mode of action of atracotoxin at central and peripheral synapses of insects. Invert Neurosci. 2003 Nov;5(1):45-50. Epub 2003 Nov 8. PMID:14608494 doi:http://dx.doi.org/10.1007/s10158-003-0027-z
- ↑ Tedford HW, Gilles N, Menez A, Doering CJ, Zamponi GW, King GF. Scanning mutagenesis of omega-atracotoxin-Hv1a reveals a spatially restricted epitope that confers selective activity against insect calcium channels. J Biol Chem. 2004 Oct 15;279(42):44133-40. Epub 2004 Aug 11. PMID:15308644 doi:http://dx.doi.org/10.1074/jbc.M404006200
- ↑ Mukherjee AK, Sollod BL, Wikel SK, King GF. Orally active acaricidal peptide toxins from spider venom. Toxicon. 2006 Feb;47(2):182-7. Epub 2005 Dec 5. PMID:16330063 doi:http://dx.doi.org/10.1016/j.toxicon.2005.10.011
- ↑ Chong Y, Hayes JL, Sollod B, Wen S, Wilson DT, Hains PG, Hodgson WC, Broady KW, King GF, Nicholson GM. The omega-atracotoxins: selective blockers of insect M-LVA and HVA calcium channels. Biochem Pharmacol. 2007 Aug 15;74(4):623-38. Epub 2007 May 25. PMID:17610847 doi:http://dx.doi.org/10.1016/j.bcp.2007.05.017
- ↑ Tedford HW, Maggio F, Reenan RA, King G. A model genetic system for testing the in vivo function of peptide toxins. Peptides. 2007 Jan;28(1):51-6. Epub 2006 Dec 1. PMID:17141372 doi:http://dx.doi.org/10.1016/j.peptides.2006.08.026
- ↑ Tedford HW, Fletcher JI, King GF. Functional significance of the beta hairpin in the insecticidal neurotoxin omega-atracotoxin-Hv1a. J Biol Chem. 2001 Jul 13;276(28):26568-76. Epub 2001 Apr 19. PMID:11313356 doi:http://dx.doi.org/10.1074/jbc.M102199200
