Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation

Noel C. Wortham, Magdalena Martinez, Yuliya Gordiyenko, Carol V. Robinson, Christopher G. Proud

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Eukaryotic initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor for eIF2 and a critical regulator of protein synthesis, (e.g., as part of the integrated stress response). Certain mutations in the EIF2B genes cause leukoencephalopathy with vanishing white matter (VWM), an often serious neurological disorder. Comprising 5 subunits, α-ε (eIF2Bε being the catalytic one), eIF2B has always been considered an αβγ δε heteropentamer. We have analyzed the subunit interactions within mammalian eIF2B by using a combination of mass spectrometry and in vivo studies of overexpressed complexes to gain further insight into the subunit arrangement of the complex. Our data reveal that eIF2B is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies of eIF2Bα.We also demonstrate a pivotal role for eIF2Bδ in the formation of eIF2B(βγδε) tetramers. eIF2B(αβ γδε)2 decamers show greater binding to eIF2 than to eIF2B(βγδε) tetramers, which may underlie the increased activity of the former. We examined the levels of eIF2B subunits in a panel of different mouse tissues and identified different levels of eIF2B subunits, particularly eIF2Bα, which implies heterogeneity in the cellular proportions of eIF2B(αβγδε) and eIF2B(βγ δε) complexes, with important implications for the regulation of translation in individual cell types.

Original languageEnglish
Pages (from-to)2225-2237
Number of pages13
JournalFASEB Journal
Volume28
Issue number5
DOIs
Publication statusPublished or Issued - May 2014
Externally publishedYes

Keywords

  • Protein synthesis
  • Vanishing white matter

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this