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Open AccessArticle

LIR Motif-Containing Hyperdisulfide β-Ginkgotide is Cytoprotective, Adaptogenic, and Scaffold-Ready

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Henry Mosberg, Tomi Sawyer, Carrie Haskell-Luevano and Stefania Galdiero
Molecules 2019, 24(13), 2417; https://doi.org/10.3390/molecules24132417
Received: 27 May 2019 / Revised: 25 June 2019 / Accepted: 28 June 2019 / Published: 30 June 2019
Grafting a bioactive peptide onto a disulfide-rich scaffold is a promising approach to improve its structure and metabolic stability. The ginkgo plant-derived β-ginkgotide β-gB1 is a highly unusual molecule: Small, hyperdisulfide, and found only in selected ancient plants. It also contains a conserved 16-amino-acid core with three interlocking disulfides, as well as a six-amino-acid inter-cysteine loop 2 suitable for grafting peptide epitopes. However, very little is known about this recently-discovered family of molecules. Here, we report the biophysical and functional characterizations of the β-ginkgotide β-gB1 from G. biloba. A circular dichroism spectroscopy analysis at 90 °C and proteolytic treatments of β-gB1 supported that it is hyperstable. Data mining revealed that the β-gB1 loop 2 contains the canonical LC3 interacting region (LIR) motif crucial for selective autophagy. Cell-based assays and pull-down experiments showed that β-gB1 is an adaptogen, able to maintain cellular homeostasis through induced autophagosomes formation and to protect cells by targeting intracellular proteins from stress-mediated damage against hypoxia and the hypoxia-reoxygenation of induced cell death. This is the first report of an LIR-containing peptide natural product. Together, our results suggest that the plant-derived β-ginkgotide is cytoprotective, capable of targeting intracellular proteins, and holds promise as a hyperdisulfide scaffold for engineering peptidyl therapeutics with enhanced structural and metabolic stability. View Full-Text
Keywords: adaptogenic; autophagy; β-ginkgotide; cytoprotective; cysteine-rich peptides; disulfide-rich scaffold; hyperdisulfide; hypoxia; LIR motif; ginkgo nuts adaptogenic; autophagy; β-ginkgotide; cytoprotective; cysteine-rich peptides; disulfide-rich scaffold; hyperdisulfide; hypoxia; LIR motif; ginkgo nuts
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MDPI and ACS Style

Dutta, B.; Huang, J.; To, J.; Tam, J.P. LIR Motif-Containing Hyperdisulfide β-Ginkgotide is Cytoprotective, Adaptogenic, and Scaffold-Ready. Molecules 2019, 24, 2417.

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