7e2k
Crystal structure of the RWD domain of human GCN2 - 1
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 PubMedGeneral control nonderepressible 2 (GCN2) is a serine/threonine protein kinase, detecting a variety of stresses including amino acid starvation, reactive oxygen species, etc. in eukaryotic cells. Activation of GCN2 requires the interaction of the N-terminal RWD domain with the upstream GCN1 protein and the dimerization by the kinase domain. In this study, we determined two crystal structures of the RWD domain of human GCN2 in two different crystal packing modes. These two different crystal structures reveal a same dimer of the RWD domain, which has not been reported in previous studies. We further confirmed this novel dimer interaction in solution using gel filtration experiments, and in human embryonic kidney (HEK) 293 cells using bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (co-IP) assays. Together, this study discovers a potential protein-protein interface on the RWD domain of human GCN2, and suggests a possible regulation between the interaction of GCN1 and the formation of GCN2 dimer. Crystal structures reveal a novel dimer of the RWD domain of human general control nonderepressible 2.,Hei Z, Wu S, Zheng L, Zhou J, Liu Z, Wang J, Fang P Biochem Biophys Res Commun. 2021 Mar 3;549:164-170. doi:, 10.1016/j.bbrc.2021.02.111. PMID:33676185[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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