Crystal structures of GCN2 protein kinase C-terminal domains suggest regulatory differences in yeast and mammals

Hongzhen He, Isha Singh, Sheree A. Wek, Souvik Dey, Thomas D. Baird, Ronald Wek, Millie Georgiadis

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

In response to amino acid starvation, GCN2 phosphorylation of eIF2 leads to repression of general translation and initiation of gene reprogramming that facilitates adaptation to nutrient stress. GCN2 is a multidomain protein with key regulatory domains that directly monitor uncharged tRNAs which accumulate during nutrient limitation, leading to activation of this eIF2 kinase and translational control. A critical feature of regulation of this stress response kinase is its C-terminal domain (CTD). Here, we present high resolution crystal structures of murine and yeast CTDs, which guide a functional analysis of the mammalian GCN2. Despite low sequence identity, both yeast and mammalian CTDs share a core subunit structure and an unusual interdigitated dimeric form, albeit with significant differences. Disruption of the dimeric form of murine CTD led to loss of translational control by GCN2, suggesting that dimerization is critical for function as is true for yeast GCN2. However, although both CTDs bind single- and double-stranded RNA, murine GCN2 does not appear to stably associate with the ribosome, whereas yeast GCN2 does. This finding suggests that there are key regulatory differences between yeast and mammalian CTDs, which is consistent with structural differences.

Original languageEnglish
Pages (from-to)15023-15034
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number21
DOIs
StatePublished - 2014

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Mammals
Yeast
Protein Kinase C
Yeasts
Crystal structure
Nutrients
Phosphotransferases
Food
Functional analysis
Phosphorylation
Double-Stranded RNA
Dimerization
Starvation
Transfer RNA
Ribosomes
Genes
Chemical activation
Amino Acids
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Crystal structures of GCN2 protein kinase C-terminal domains suggest regulatory differences in yeast and mammals. / He, Hongzhen; Singh, Isha; Wek, Sheree A.; Dey, Souvik; Baird, Thomas D.; Wek, Ronald; Georgiadis, Millie.

In: Journal of Biological Chemistry, Vol. 289, No. 21, 2014, p. 15023-15034.

Research output: Contribution to journalArticle

He, Hongzhen ; Singh, Isha ; Wek, Sheree A. ; Dey, Souvik ; Baird, Thomas D. ; Wek, Ronald ; Georgiadis, Millie. / Crystal structures of GCN2 protein kinase C-terminal domains suggest regulatory differences in yeast and mammals. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 21. pp. 15023-15034.
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