7qq6

Structural highlights

Disease

E2AK4_HUMAN Pulmonary venoocclusive disease;Pulmonary capillary hemangiomatosis;Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry.

Function

E2AK4_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]

References

1. ↑ Roobol A, Roobol J, Bastide A, Knight JR, Willis AE, Smales CM. p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem J. 2015 Jan 15;465(2):213-25. doi: 10.1042/BJ20140852. PMID:25329545 doi:http://dx.doi.org/10.1042/BJ20140852
2. ↑ Lehman SL, Cerniglia GJ, Johannes GJ, Ye J, Ryeom S, Koumenis C. Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. PLoS Genet. 2015 Jun 23;11(6):e1005212. doi: 10.1371/journal.pgen.1005212., eCollection 2015 Jun. PMID:26102367 doi:http://dx.doi.org/10.1371/journal.pgen.1005212
3. ↑ Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J, Maddur MS, Park Y, Jones DP, Chappert P, Davoust J, Weiss DS, Virgin HW, Ron D, Pulendran B. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science. 2014 Jan 17;343(6168):313-317. doi: 10.1126/science.1246829. Epub 2013, Dec 5. PMID:24310610 doi:http://dx.doi.org/10.1126/science.1246829
4. ↑ Maia de Oliveira T, Korboukh V, Caswell S, Winter Holt JJ, Lamb M, Hird AW, Overman R. The structure of human GCN2 reveals a parallel, back-to-back kinase dimer with a plastic DFG activation loop motif. Biochem J. 2020 Jan 17;477(1):275-284. PMID:31868900 doi:10.1042/BCJ20190196