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The mechanistic insight of a specific interaction between 15d-Prostaglandin-J2 and eIF4A suggests an evolutionary conserved role across species

Title
The mechanistic insight of a specific interaction between 15d-Prostaglandin-J2 and eIF4A suggests an evolutionary conserved role across species
Authors
Yun, S.J.Kim, H.Jung, S.-H.Kim, J.H.Ryu, J.E.Jiten Singh, N.Jeon, J.Han, J.-K.Kim, C.-H.Kim, S.Jang, S.K.Kim, W.J.
Date Issued
Nov-2018
Publisher
Company of Biologists Ltd
Abstract
15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory/anti-neoplastic prostaglandin that functions through covalent binding to cysteine residues of various target proteins. We previously showed that 15d-PGJ2 mediated anti-inflammatory responses are dependent on the translational inhibition through its interaction with eIF4A (Kim et al., 2007). Binding of 15d-PGJ2 to eIF4A specifically blocks the interaction between eIF4G and eIF4A, which leads to the formation of stress granules (SGs), which then cluster mRNAs with inhibited translation. Here, we show that the binding between 15d-PGJ2 and eIF4A specifically blocks the interaction between the MIF4G domain of eIF4G and eIF4A. To reveal the mechanism of this interaction, we used computational simulation-based docking studies and identified that the carboxyl tail of 15d-PGJ2 could stabilize the binding of 15d-PGJ2 to eIF4A through arginine 295 of eIF4A, which is the first suggestion that the 15d-PGJ2 tail plays a physiological role. Interestingly, the putative 15d-PGJ2 binding site on eiF4A is conserved across many species, suggesting a biological role. Our data propose that studying 15d-PGJ2 and its targets may uncover new therapeutic approaches in anti-inflammatory drug discovery. © 2018. Published by The Company of Biologists Ltd
URI
http://oasis.postech.ac.kr/handle/2014.oak/95006
ISSN
2046-6390
Article Type
Article
Citation
Biology Open, vol. 7, no. 11, 2018-11
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 HAN, JIN KWAN
Dept of Life Sciences
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