Title

Identification of a novel class of nicotinic receptor antagonists: dimeric conotoxins VxXIIA, VxXIIB, and VxXIIC from Conus vexillum

RIS ID

105730

Publication Details

Loughnan, M., Nicke, A., Jones, A., Schroeder, C. I., Nevin, S. T., Adams, D. J., Alewood, P. F. & Lewis, R. J. (2006). Identification of a novel class of nicotinic receptor antagonists: dimeric conotoxins VxXIIA, VxXIIB, and VxXIIC from Conus vexillum. Journal of Biological Chemistry, 281 (34), 24745-24755.

Abstract

The venoms of predatory marine snails (Conus spp.) contain diverse mixtures of peptide toxins with high potency and selectivity for a variety of voltage-gated and ligand-gated ion channels. Here we describe the chemical and functional characterization of three novel conotoxins, αD-VxXIIA, αD-VxXIIB, and αD-VxXIIC, purified from the venom of Conus vexillum. Each toxin was observed as an ∼11-kDa protein by LC/MS, size exclusion chromatography, and SDS-PAGE. After reduction, the peptide sequences were determined by Edman degradation chemistry and tandem MS. Combining the sequence data together with LC/MS and NMR data revealed that in solution these toxins are pseudo-homodimers of paired 47-50-residue peptides. The toxin subunits exhibited a novel arrangement of 10 conserved cystine residues, and additional post-translational modifications contributed heterogeneity to the proteins. Binding assays and two-electrode voltage clamp analyses showed that αD-VxXIIA, αD-VxXIIB, and αD-VxXIIC are potent inhibitors of nicotinic acetylcholine receptors (nAChRs) with selectivity for α7 and β2 containing neuronal nAChR subtypes. These dimeric conotoxins represent a fifth and highly divergent structural class of conotoxins targeting nAChRs.

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Link to publisher version (DOI)

http://dx.doi.org/10.1074/jbc.M603703200