Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase

Daiki Hayashi, Varnavas D. Mouchlis, Seika Okamoto, Tomoka Namba, Liuqing Wang, Sheng Li, Shuji Ueda, Minoru Yamanoue, Hirofumi Tachibana, Hiroyuki Arai, Hitoshi Ashida, Edward A. Dennis, Yasuhito Shirai

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number109129
JournalJournal of Nutritional Biochemistry
Volume110
DOIs
Publication statusPublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry

Fingerprint

Dive into the research topics of 'Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase'. Together they form a unique fingerprint.

Cite this