Protein: Eukaryotic translation initiation factor 2-alpha kinase 1 (Q9BQI3)
Organism: Homo sapiens (Human)
Function: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions . Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming . Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Iron deficiency also triggers activation by full-length DELE1. Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming
InterPro domains:
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [438-450]
- IPR000719: Protein kinase domain (domain) [167-583]
- IPR017441: Protein kinase, ATP binding site (binding_site) [173-197]
- IPR054521: Heme-regulated eIF-2-alpha kinase, helical domain (domain) [63-141]
- IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [161-591]
- IPR050339: Cell Cycle and Stress Response Kinase (family) [97-608]
Sequence:
MQGGNSGVRKREEEGDGAGAVAAPPAIDFPAEGPDPEYDESDVPAEIQVLKEPLQQPTFPFAVANQLLLVSLLEHLSHVHEPNPLRSRQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHHNRAITHLMRSAKERVRQDPCEDISRIQKIRSREVALEAQTSRYLNEFEELAILGKGGYGRVYKVRNKLDGQYYAIKKILIKGATKTVCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVIQPRADRAAIELPSLEVLSDQEEDREQCGVKNDESSSSSIIFAEPTPEKEKRFGESDTENQNNKSVKYTTNLVIRESGELESTLELQENGLAGLSASSIVEQQLPLRRNSHLEESFTSTEESSEENVNFLGQTEAQYHLMLHIQMQLCELSLWDWIVERNKRGREYVDESACPYVMANVATKIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACTDILQKNTDWTNRNGKRTPTHTSRVGTCLYASPEQLEGSEYDAKSDMYSLGVVLLELFQPFGTEMERAEVLTGLRTGQLPESLRKRCPVQAKYIQHLTRRNSSQRPSAIQLLQSELFQNSGNVNLTLQMKIIEQEKEIAELKKQLNLLSQDKGVRDDGKDGGVG
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0045182 (translation regulator activity), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0004694 (eukaryotic translation initiation factor 2alpha kinase activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0004672 (protein kinase activity), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0009987 (cellular process), GO:0050896 (response to stimulus), GO:0009605 (response to external stimulus), GO:0051716 (cellular response to stimulus), GO:0006950 (response to stress), GO:0009991 (response to extracellular stimulus), GO:0042594 (response to starvation), GO:0033554 (cellular response to stress), GO:0140467 (integrated stress response signaling), GO:1990641 (response to iron ion starvation), GO:0031667 (response to nutrient levels)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure), GO:0005737 (cytoplasm)