Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase
Copyright © 2022. Published by Elsevier Inc..
It is generally recognized that the main function of α-tocopherol (αToc), which is the most active form of vitamin E, is its antioxidant effect, while non-antioxidant effects have also been reported. We previously found that αToc ameliorates diabetic nephropathy via diacylglycerol kinase alpha (DGKα) activation in vivo, and the activation was not related to the antioxidant effect. However, the underlying mechanism of how αToc activates DGKα have been enigmatic. We report that the membrane-bound 67 kDa laminin receptor (67LR), which has previously been shown to serve as a receptor for epigallocatechin gallate (EGCG), also contains a novel binding site for vitamin E, and its association with Vitamin E mediates DGKα activation by αToc. We employed hydrogen-deuterium exchange mass spectrometry (HDX/MS) and molecular dynamics (MD) simulations to identify the specific binding site of αToc on the 67LR and discovered the conformation of the specific hydrophobic pocket that accommodates αToc. Also, HDX/MS and MD simulations demonstrated the detailed binding of EGCG to a water-exposed hydrophilic site on 67LR, while in contrast αToc binds to a distinct hydrophobic site. We demonstrated that 67LR triggers an important signaling pathway mediating non-antioxidant effects of αToc, such as DGKα activation. This is the first evidence demonstrating a membrane receptor for αToc and one of the underlying mechanisms of a non-antioxidant function for αToc.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:110 |
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| Enthalten in: |
The Journal of nutritional biochemistry - 110(2022) vom: 01. Dez., Seite 109129 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hayashi, Daiki [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.11.2022 Date Revised 02.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jnutbio.2022.109129 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM344962822 |
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| 100 | 1 | |a Hayashi, Daiki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase |
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| 500 | |a Date Revised 02.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022. Published by Elsevier Inc. | ||
| 520 | |a It is generally recognized that the main function of α-tocopherol (αToc), which is the most active form of vitamin E, is its antioxidant effect, while non-antioxidant effects have also been reported. We previously found that αToc ameliorates diabetic nephropathy via diacylglycerol kinase alpha (DGKα) activation in vivo, and the activation was not related to the antioxidant effect. However, the underlying mechanism of how αToc activates DGKα have been enigmatic. We report that the membrane-bound 67 kDa laminin receptor (67LR), which has previously been shown to serve as a receptor for epigallocatechin gallate (EGCG), also contains a novel binding site for vitamin E, and its association with Vitamin E mediates DGKα activation by αToc. We employed hydrogen-deuterium exchange mass spectrometry (HDX/MS) and molecular dynamics (MD) simulations to identify the specific binding site of αToc on the 67LR and discovered the conformation of the specific hydrophobic pocket that accommodates αToc. Also, HDX/MS and MD simulations demonstrated the detailed binding of EGCG to a water-exposed hydrophilic site on 67LR, while in contrast αToc binds to a distinct hydrophobic site. We demonstrated that 67LR triggers an important signaling pathway mediating non-antioxidant effects of αToc, such as DGKα activation. This is the first evidence demonstrating a membrane receptor for αToc and one of the underlying mechanisms of a non-antioxidant function for αToc | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a 67 kDa laminin receptor | |
| 650 | 4 | |a diabetic nephrophaty | |
| 650 | 4 | |a diacylglycerol kinase | |
| 650 | 4 | |a epigallocatechin gallate | |
| 650 | 4 | |a vitamin E | |
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| 650 | 7 | |a EC 2.7.1.107 |2 NLM | |
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| 650 | 7 | |a Catechin |2 NLM | |
| 650 | 7 | |a 8R1V1STN48 |2 NLM | |
| 650 | 7 | |a alpha-Tocopherol |2 NLM | |
| 650 | 7 | |a H4N855PNZ1 |2 NLM | |
| 650 | 7 | |a Antioxidants |2 NLM | |
| 700 | 1 | |a Mouchlis, Varnavas D |e verfasserin |4 aut | |
| 700 | 1 | |a Okamoto, Seika |e verfasserin |4 aut | |
| 700 | 1 | |a Namba, Tomoka |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Liuqing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Ueda, Shuji |e verfasserin |4 aut | |
| 700 | 1 | |a Yamanoue, Minoru |e verfasserin |4 aut | |
| 700 | 1 | |a Tachibana, Hirofumi |e verfasserin |4 aut | |
| 700 | 1 | |a Arai, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Ashida, Hitoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Dennis, Edward A |e verfasserin |4 aut | |
| 700 | 1 | |a Shirai, Yasuhito |e verfasserin |4 aut | |
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