Mechanisms of translational regulation by a human eIF5-mimic protein

Chingakham Ranjit Singh, Ryosuke Watanabe, Donghui Zhou, Martin D. Jennings, Akira Fukao, Bumjun Lee, Yuka Ikeda, John A. Chiorini, Susan G. Campbell, Mark P. Ashe, Toshinobu Fujiwara, Ronald C. Wek, Graham D. Pavitt, Katsura Asano

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNAi Met ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function.

Original languageEnglish (US)
Pages (from-to)8314-8328
Number of pages15
JournalNucleic acids research
Volume39
Issue number19
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Genetics

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    Singh, C. R., Watanabe, R., Zhou, D., Jennings, M. D., Fukao, A., Lee, B., Ikeda, Y., Chiorini, J. A., Campbell, S. G., Ashe, M. P., Fujiwara, T., Wek, R. C., Pavitt, G. D., & Asano, K. (2011). Mechanisms of translational regulation by a human eIF5-mimic protein. Nucleic acids research, 39(19), 8314-8328. https://doi.org/10.1093/nar/gkr339