Gcn2

GCN2, or general control nonderepressible 2, is a conserved serine/threonine-protein kinase that acts as a central sensor and regulator of cellular responses to amino acid deprivation in eukaryotes. In yeast, it is the key kinase of the general amino acid control (GAAC) pathway, while in mammals it is a component of the integrated stress response (ISR) that helps coordinate adaptation to nutrient stress.

The activation of GCN2 is driven by the accumulation of uncharged transfer RNAs during amino acid starvation. Its N-terminal regulatory region contains a histidyl-tRNA synthetase–like domain that binds uncharged tRNA, and, together with interaction with cofactors such as Gcn1, relays the amino acid status to the kinase domain. Binding of uncharged tRNA relieves autoinhibition and promotes activation of the C-terminal kinase domain, which phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α) on serine 51. This phosphorylation reduces global protein synthesis while allowing selective translation of specific mRNAs, notably GCN4 in yeast and ATF4 in mammals, which in turn drive transcription of amino acid biosynthesis genes or stress-responsive genes.

Structure-wise, GCN2 comprises an N-terminal regulatory region with the tRNA–binding–like domain and a C-terminal serine/threonine kinase domain, with an overall architecture that enables sensing of amino acid deficiency at the ribosome via associated factors such as Gcn1.

Clinical relevance in humans is linked to EIF2AK4, the GCN2-encoding gene; mutations can cause pulmonary veno-occlusive disease and related conditions. Beyond this, GCN2 participates in broader stress responses relevant to cancer biology, neurodegeneration, and metabolic regulation, reflecting its pivotal role in connecting nutrient status to gene expression and proteome remodeling.