Venomous marine cone snails produce peptide toxins (conotoxins) that bind ion channels and receptors with high specificity and therefore are important pharmacological tools. Conotoxins contain conserved cysteine residues that form disulfide bonds that stabilize their structures. To gain structural insight into the large, yet poorly characterized conotoxin H-superfamily, we used NMR and CD spectroscopy along with MS-based analyses to investigate H-Vc7.2 from Conus victoriae, a peptide with a VI/VII cysteine framework. This framework has Cys I-Cys IV /Cys II-Cys V /Cys III-Cys VI connectivities, which have invariably been associated with the inhibitor cystine knot (ICK) fold. However, the solution structure of recombinantly expressed and purified H-Vc7.2 revealed that although it displays the expected cysteine connectivities, H-Vc7.2 adopts a different fold consisting of two stacked -hairpins with opposing -strands connected by two parallel disulfide bonds, a structure homologous to the N-terminal region of the human granulin protein. Using structural comparisons, we subsequently identified several toxins and nontoxin proteins with this "mini-granulin" fold. These findings raise fundamental questions concerning sequence-structure relationships within peptides and proteins and the key determinants that specify a given fold. Venoms from a variety of animals such as snakes, spiders, scorpions, and marine snails contain diverse peptide toxins that This work was supported in part by Danish Council for Independent Research Technology and Production Sciences Grant 7017-00288, Ulla og Mogens Folmer Andersens Fond, Fondation Juchum and Hørslev-Fonden (L. E.), and the Velux Foundations (K. T.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S6, Tables S1-S6, and supporting Ref. 1. The atomic coordinates and structure factors (code 6Q5Z) have been deposited in the Protein Data Bank (http://wwpdb.org/). Chemical shifts have been deposited in the Biological Magnetic Resonance Bank with ID 34335.
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