LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready
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 conserv...
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sg-ntu-dr.10356-795192023-02-28T16:58:44Z LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready Dutta, Bamaprasad Huang, Jiayi To, Janet Tam, James P. School of Biological Sciences Science::Biological sciences Adaptogenic Autophagy 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. MOE (Min. of Education, S’pore) Published version 2019-08-21T02:23:09Z 2019-12-06T13:27:18Z 2019-08-21T02:23:09Z 2019-12-06T13:27:18Z 2019 Journal Article Dutta, B., Huang, J., To, J., & Tam, J. P. (2019). LIR Motif-Containing Hyperdisulfide β-Ginkgotide is Cytoprotective, Adaptogenic, and Scaffold-Ready. Molecules, 24(13), 2417-. doi:10.3390/molecules24132417 1420-3049 https://hdl.handle.net/10356/79519 http://hdl.handle.net/10220/49718 10.3390/molecules24132417 en Molecules © 2019 by the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 14 p. application/pdf |
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Science::Biological sciences Adaptogenic Autophagy Dutta, Bamaprasad Huang, Jiayi To, Janet Tam, James P. LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
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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. |
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School of Biological Sciences |
author_facet |
School of Biological Sciences Dutta, Bamaprasad Huang, Jiayi To, Janet Tam, James P. |
format |
Article |
author |
Dutta, Bamaprasad Huang, Jiayi To, Janet Tam, James P. |
author_sort |
Dutta, Bamaprasad |
title |
LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
title_short |
LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
title_full |
LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
title_fullStr |
LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
title_full_unstemmed |
LIR motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
title_sort |
lir motif-containing hyperdisulfide β-ginkgotide is cytoprotective, adaptogenic, and scaffold-ready |
publishDate |
2019 |
url |
https://hdl.handle.net/10356/79519 http://hdl.handle.net/10220/49718 |
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1759853183834783744 |