Disulfide rich peptides (DRPs) play diverse physiological roles and have emerged as attractive sources of pharmacological tools and drug leads. Here we describe the 3D structure of a centipede venom peptide that defines a new class of one of the most widespread DRP folds known, the cystine-stabilised α/β fold (CSαβ). This new class, which we have named the two-disulfide CSαβ fold (2ds-CSαβ), contains only two internal disulfide bonds as opposed to at least three in all other confirmed CSαβ peptides, and constitutes one of the major neurotoxic peptide families in giant centipede venoms. We show the 2ds-CSαβ is also widely distributed outside centipedes, and probably shares an evolutionary origin with all other CSαβ that predates the split between prokaryotes and eukaryotes. Our results highlight the usefulness of 3D structures as evolutionary tools and provides some of the first insights into the ancient evolutionary history of any DRP fold.
Dash, Thomas S. and Shafee, Thomas and Harvey, Peta J. and Zhang, Chuchu and Peigneur, Steve and Deuis, Jennifer R. and Vetter, Irina and Tytgat, Jan and Anderson, Marilyn and Craik, David J. and Durek, Thomas and Undheim, Eivind A. B., A Centipede Toxin Family Defines a New Ancient Class of CSαβ Defensins (2018). Available at SSRN: https://ssrn.com/abstract=3188389 or http://dx.doi.org/10.2139/ssrn.3188389
This version of the paper has not been formally peer reviewed.
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