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  • The EMBO Journal (2006) 25, 4537 - 4546
  • doi:10.1038/sj.emboj.7601339

Published online: 21 September 2006

An eIF5/eIF2 complex antagonizes guanine nucleotide exchange by eIF2B during translation initiation

Chingakham Ranjit Singh1,a, Bumjun Lee1,a, Tsuyoshi Udagawa1, Sarah S Mohammad-Qureshi2, Yasufumi Yamamoto1, Graham D Pavitt2 and Katsura Asano1

  1. Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS, USA
  2. Faculty of Life Sciences, The University of Manchester, Manchester, UK

Correspondence to:

Katsura Asano, Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA. Tel.: +1 785 532 0116; Fax: +1 785 532 6653; E-mail: kasano@ksu.edu

Graham D Pavitt, Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK. E-mail: graham.pavitt@manchester.ac.uk

aThese authors contributed equally to this work

Received 9 May 2006; Accepted 18 August 2006

In eukaryotic translation initiation, the eIF2dotGTP/Met-tRNAiMet ternary complex (TC) binds the eIF3/eIF1/eIF5 complex to form the multifactor complex (MFC), whereas eIF2dotGDP binds the pentameric factor eIF2B for guanine nucleotide exchange. eIF5 and the eIF2Balt epsilon catalytic subunit possess a conserved eIF2-binding site. Nearly half of cellular eIF2 forms a complex with eIF5 lacking Met-tRNAiMet, and here we investigate its physiological significance. eIF5 overexpression increases the abundance of both eIF2/eIF5 and TC/eIF5 complexes, thereby impeding eIF2B reaction and MFC formation, respectively. eIF2Balt epsilon mutations, but not other eIF2B mutations, enhance the ability of overexpressed eIF5 to compete for eIF2, indicating that interaction of eIF2Balt epsilon with eIF2 normally disrupts eIF2/eIF5 interaction. Overexpression of the catalytic eIF2Balt epsilon segment similarly exacerbates eIF5 mutant phenotypes, supporting the ability of eIF2Balt epsilon to compete with MFC. Moreover, we show that eIF5 overexpression does not generate aberrant MFC lacking tRNAiMet, suggesting that tRNAiMet is a vital component promoting MFC assembly. We propose that the eIF2/eIF5 complex represents a cytoplasmic reservoir for eIF2 that antagonizes eIF2B-promoted guanine nucleotide exchange, enabling coordinated regulation of translation initiation.

  • Keywords:

    • eIF,
    • GTPase activation,
    • guanine nucleotide exchange,
    • ribosomal preinitiation complex,
    • translation initiation