Eukaryotic translation initiation factor 2-alpha kinase 1 (EC 2.7.11.1) (Heme-controlled repressor) (HCR) (Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase) (Heme-regulated inhibitor) (hHRI) (Hemin-sensitive initiation factor 2-alpha kinase)
1_MQGGN 6_ SGVRK 11_ REEEG 16_ DGAGA 21_ VAAPP 26_ AIDFP 31_ AEGPD 36_ PEYDE 41_ SDVPA 46_ EIQVL 51_ KEPLQ 56_ QPTFP 61_ FAVAN 66_ QLLLV 71_ SLLEH 76_ LSHVH 81_ EPNPL 86_ RSRQV 91_ FKLLC 96_ QTFIK 101_ MGLLS 106_ SFTCS 111_ DEFSS 116_ LRLHH 121_ NRAIT 126_ HLMRS 131_ AKERV 136_ RQDPC 141_ EDISR 146_ IQKIR 151_ SREVA 156_ LEAQT 161_ SRYLN 166_ EFEEL 171_ AILGK 176_ GGYGR 181_ VYKVR 186_ NKLDG 191_ QYYAI 196_ KKILI 201_ KGATK 206_ TVCMK 211_ VLREV 216_ KVLAG 221_ LQHPN 226_ IVGYH 231_ TAWIE 236_ HVHVI 241_ QPRAD 246_ RAAIE 251_ LPSLE 256_ VLSDQ 261_ EEDRE 266_ QCGVK 271_ NDESS 276_ SSSII 281_ FAEPT 286_ PEKEK 291_ RFGES 296_ DTENQ 301_ NNKSV 306_ KYTTN 311_ LVIRE 316_ SGELE 321_ STLEL 326_ QENGL 331_ AGLSA 336_ SSIVE 341_ QQLPL 346_ RRNSH 351_ LEESF 356_ TSTEE 361_ SSEEN 366_ VNFLG 371_ QTEAQ 376_ YHLML 381_ HIQMQ 386_ LCELS 391_ LWDWI 396_ VERNK 401_ RGREY 406_ VDESA 411_ CPYVM 416_ ANVAT 421_ KIFQE 426_ LVEGV 431_ FYIHN 436_ MGIVH 441_ RDLKP 446_ RNIFL 451_ HGPDQ 456_ QVKIG 461_ DFGLA 466_ CTDIL 471_ QKNTD 476_ WTNRN 481_ GKRTP 486_ THTSR 491_ VGTCL 496_ YASPE 501_ QLEGS 506_ EYDAK 511_ SDMYS 516_ LGVVL 521_ LELFQ 526_ PFGTE 531_ MERAE 536_ VLTGL 541_ RTGQL 546_ PESLR 551_ KRCPV 556_ QAKYI 561_ QHLTR 566_ RNSSQ 571_ RPSAI 576_ QLLQS 581_ ELFQN 586_ SGNVN 591_ LTLQM 596_ KIIEQ 601_ EKEIA 606_ ELKKQ 611_ LNLLS 616_ QDKGV 621_RDDGK
1: 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 (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). 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 (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). 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 (PubMed:32132706, PubMed:32132707, PubMed:37327776). 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 (PubMed:37327776). 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 (PubMed:32132706, PubMed:32132707). Also acts as an activator of mitophagy in response to mitochondrial damage: catalyzes phosphorylation of eIF-2-alpha (EIF2S1) following activation by S-DELE1, thereby promoting mitochondrial localization of EIF2S1, triggering PRKN-independent mitophagy (PubMed:38340717)