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Int. J. Mol. Sci. 2018, 19(11), 3418; https://doi.org/10.3390/ijms19113418

Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins

1
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA
2
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai 980-8577, Japan
3
Department of Biology, University of Copenhagen, 2200 Copenhagen N., Denmark
4
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
Current address: School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan.
*
Author to whom correspondence should be addressed.
Received: 8 October 2018 / Revised: 22 October 2018 / Accepted: 23 October 2018 / Published: 31 October 2018
(This article belongs to the Special Issue Molecular Chaperones)
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Abstract

Disulfide-rich peptides are highly abundant in nature and their study has provided fascinating insight into protein folding, structure and function. Venomous cone snails belong to a group of organisms that express one of the largest sets of disulfide-rich peptides (conotoxins) found in nature. The diversity of structural scaffolds found for conotoxins suggests that specialized molecular adaptations have evolved to ensure their efficient folding and secretion. We recently showed that canonical protein disulfide isomerase (PDI) and a conotoxin-specific PDI (csPDI) are ubiquitously expressed in the venom gland of cone snails and play a major role in conotoxin folding. Here, we identify cone snail endoplasmic reticulum oxidoreductin-1 (Conus Ero1) and investigate its role in the oxidative folding of conotoxins through reoxidation of cone snail PDI and csPDI. We show that Conus Ero1 preferentially reoxidizes PDI over csPDI, suggesting that the reoxidation of csPDI may rely on an Ero1-independent molecular pathway. Despite the preferential reoxidation of PDI over csPDI, the combinatorial effect of Ero1 and csPDI provides higher folding yields than Ero1 and PDI. We further demonstrate that the highest in vitro folding rates of two model conotoxins are achieved when all three enzymes are present, indicating that these enzymes may act synergistically. Our findings provide new insight into the generation of one of the most diverse classes of disulfide-rich peptides and may improve current in vitro approaches for the production of venom peptides for pharmacological studies. View Full-Text
Keywords: cone snail toxins; disulfide-rich venom peptides; endoplasmic reticulum oxidoreductin-1 (Ero1); protein disulfide isomerase (PDI) cone snail toxins; disulfide-rich venom peptides; endoplasmic reticulum oxidoreductin-1 (Ero1); protein disulfide isomerase (PDI)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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O’Brien, H.; Kanemura, S.; Okumura, M.; Baskin, R.P.; Bandyopadhyay, P.K.; Olivera, B.M.; Ellgaard, L.; Inaba, K.; Safavi-Hemami, H. Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins. Int. J. Mol. Sci. 2018, 19, 3418.

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