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TitleGCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.
Journal, issue, pagesScience, Vol. 390, Issue 6768, Page eads8728, Year 2025
Publish dateOct 2, 2025
AuthorsChangqian Zhou / Miao Zhang / Jason Murray / Joao Paulo / Steve Gygi / Sichen Shao / Malcolm Whitman / Tracy Keller /
PubMed AbstractDuring nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular ...During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.
External linksScience / PubMed:41037622
MethodsEM (single particle)
Resolution3.3 Å
Structure data

43189

8vft

EMDB-43189, PDB-8vft:
Translating 80S rabbit ribosome stalled by emetine with eEF2
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-34G:
emetine

Source
  • oryctolagus cuniculus (rabbit)
KeywordsRIBOSOME / stalled ribosome / tRNAs / eEF2

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