9yak
Structure of the GCN2 pseudokinase domain
Structural highlights
DiseaseE2AK4_HUMAN Pulmonary venoocclusive disease;Pulmonary capillary hemangiomatosis;Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. FunctionE2AK4_HUMAN Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the 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 ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity).[UniProtKB:P15442][UniProtKB:Q9QZ05][1] [2] (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610).[3] Publication Abstract from PubMedThe general control nonderepressible 2 (GCN2) is a conserved stress-responsive protein that plays a critical role in restoring cellular homeostasis in the integrated stress response (ISR). In response to amino acid starvation or ribosome stalling and collisions, GCN2 phosphorylates the translation initiation factor eIF2alpha, conferring translational control to alleviate stress. GCN2 is a multidomain protein, containing a tandem kinase domain (KD) and a catalytically inactive pseudokinase domain (psiKD). Stress-induced activation of the kinase domain requires allosteric regulation and dimerization mediated by its regulatory domains. While the pseudokinase domain is essential for GCN2 function in yeast, its mechanistic role remains unclear and underexplored in other organisms. Here, we present the first crystal structure of the human GCN2 psiKD, revealing its distinct structural features. The structure visualizes an insertion N-terminal to helix alphaC unique to the GCN2 psiKD that interacts with the pseudoactivation loop, stabilizing an inactive conformation. Further structural analysis shows that the psiKD forms a dimer in the crystal lattice via a network of hydrophobic and electrostatic interactions spanning both the N- and C-lobes. Mutations that disrupt the dimer interface reduced downstream ATF4 expression that is important for stress adaptation, underscoring the functional significance of the GCN2 psiKD dimer in regulating GCN2 activity. Complementary AI-guided structure predictions indicate that the dimeric GCN2 psiKD architecture is conserved across evolution. These results support the role of psiKD dimerization as a regulatory feature in GCN2-mediated ISR signaling. Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.,Liu Y, Misra J, Bhowmik DR, O'Boyle B, Staschke KA, Kannan N, Wek RC, Jura N Proc Natl Acad Sci U S A. 2026 Feb 3;123(5):e2526598123. doi: , 10.1073/pnas.2526598123. Epub 2026 Jan 30. PMID:41615758[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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