8t7t | pdb_00008t7t
CryoEM structure of the HisRS-like domain of human GCN2
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 PubMedGCN2 is a stress response kinase that phosphorylates the translation initiation factor eIF2alpha to inhibit general protein synthesis when activated by uncharged tRNA and stalled ribosomes. The presence of a HisRS-like domain in GCN2, normally associated with tRNA aminoacylation, led to the hypothesis that eIF2alpha kinase activity is regulated by the direct binding of this domain to uncharged tRNA. Here we solved the structure of the HisRS-like domain in the context of full-length GCN2 by cryoEM. Structure and function analysis shows the HisRS-like domain of GCN2 has lost histidine and ATP binding but retains tRNA binding abilities. Hydrogen deuterium exchange mass spectrometry, site-directed mutagenesis and computational docking experiments support a tRNA binding model that is partially shifted from that employed by bona fide HisRS enzymes. These results demonstrate that the HisRS-like domain of GCN2 is a pseudoenzyme and advance our understanding of GCN2 regulation and function. The HisRS-like domain of GCN2 is a pseudoenzyme that can bind uncharged tRNA.,Yin JZ, Keszei AFA, Houliston S, Filandr F, Beenstock J, Daou S, Kitaygorodsky J, Schriemer DC, Mazhab-Jafari MT, Gingras AC, Sicheri F Structure. 2024 Jun 6;32(6):795-811.e6. doi: 10.1016/j.str.2024.02.021. Epub 2024 , Mar 25. PMID:38531363[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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