Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/SUI2) on 'Ser-52' in response to low amino acid, carbon, or purine availability (PubMed:1739968, PubMed:7623840, PubMed:8798780, PubMed:9528799, PubMed:10983975, PubMed:17202131, PubMed:8336737, PubMed:10733573). Plays a role as an activator of the general amino acid control (GAAC) pathway required for adapatation to nutrient starvation. Converts phosphorylated eIF-2-alpha/SUI2 either to a competitive inhibitor of translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator GCN4, and hence allowing GCN4-mediated reprogramming of transcription to alleviate nutrient depletion (PubMed:2660141, PubMed:2188100, PubMed:1739968, PubMed:7621831, PubMed:7623840, PubMed:8798780, PubMed:10801780, PubMed:11350982, PubMed:24333428, PubMed:10733573). Binds uncharged tRNAs (PubMed:7623840, PubMed:10983975). (orthologuous-specific) Binds to aminoacylated tRNA(Phe) less tightly than to deacylated tRNA(Phe) (PubMed:10983975). Binds to double-stranded RNA (PubMed:9430731). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] The kinase activity is stimulated upon binding to uncharged tRNAs (PubMed:7623840). Homodimer; homodimerization is important for kinase activation by uncharged tRNAs (PubMed:9566889, PubMed:10983975, PubMed:11250908, PubMed:17202131, PubMed:15964839). Interacts (via N-terminal RWD domain) with GCN1 (via N- and C-terminus); this interaction stimulates GCN2 kinase activity in a GCN20-dependent manner in response to amino acid starvation (PubMed:10775272, PubMed:11101534, PubMed:10801780, PubMed:11350982, PubMed:21849502). Interacts (via N-terminus) with the GCN1-GCN20 complex on translating ribosomes in amino acid-starved cells; GCN1 may bind near the ribosomal A-site and promotes the transfer of uncharged tRNAs from the A-site to the tRNA-binding domain in GCN2 for its subsequent kinase activation, and hence allowing GCN4 translational activation and derepression of amino acid biosynthetic genes (PubMed:10775272, PubMed:11101534). Interacts (via C-terminus) with TIF11; this interaction is direct, occurs in amino acid-repleted cells, may be stabilzed in a ribosome-dependent manner, reduces GCN2-mediated eIF-2-alpha phosphorylation but not GCN2 autophosphorylation and is lost in amino acid-starved cells and by uncharged tRNAs (PubMed:21849502). Associates (via C-terminus) with ribosomes (PubMed:2038314, PubMed:9430731, PubMed:10983975, PubMed:22888004). The C-terminal domain negatively regulates kinase activity via an autoinhibitory association with the protein kinase and histidyl-tRNA synthetase-like domains in amino acid-repleted cells, that is counteracted by uncharged tRNAs in amino acid-starved cells (PubMed:7623840, PubMed:8798780, PubMed:10983975, PubMed:11250908). The C-terminal, histidyl-tRNA synthetase-like region and protein kinase domains are necessary for homodimer formation (PubMed:9566889, PubMed:10983975, PubMed:11250908). The C-terminal and protein kinase domains are necessary for ribosome association (PubMed:9566889, PubMed:10983975). The C-terminal and histidyl-tRNA synthetase-like regions are required for uncharged tRNAs binding in amino acid-starved cells (PubMed:7623840, PubMed:8798780, PubMed:9430731, PubMed:10983975). Autophosphorylated, autophosphorylation on Thr-882 and Thr-887 increases kinase activity. Abolishes phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/SUI2) during amino acid, purine, and glucose starvation (PubMed:8336737, PubMed:10733573). Inhibits GCN4 derepression in glucose, amino acid, or purine-starved cells (PubMed:8336737, PubMed:10733573). Decreases vacuolar free amino acid levels during glucose starvation (PubMed:10733573). Sensitive to the purine analog 8-azaadenine (PubMed:8336737). Increases duration of lag phase on return to glucose-rich medium following glucose starvation (PubMed:10733573). Present with 279 molecules/cell in log phase SD medium. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.