CPLM-020054

Genbank Nucleotide ID

Eukaryotic translation initiation factor 2-alpha kinase 1

Protein Synonyms/Alias

Heme-controlled repressor; HCR; Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase; Heme-regulated inhibitor; Hemin-sensitive initiation factor 2-alpha kinase

HRI; KIAA1369; PRO1362

Homo sapiens (Human)

Position	Peptide	Type	References
175	EELAILGKGGYGRVY	ubiquitination	[1]
302	DTENQNNKSVKYTTN	ubiquitination	[1]

[1] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]

Functional Description

Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser- 48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions (By similarity).

DOMAIN 167 583 Protein kinase.
REPEAT 410 415 HRM 1.
REPEAT 552 557 HRM 2.
NP_BIND 173 181 ATP (By similarity).
ACT_SITE 442 442 Proton acceptor (By similarity).
BINDING 196 196 ATP (By similarity).
MOD_RES 486 486 Phosphothreonine; by autocatalysis (By
MOD_RES 488 488 Phosphothreonine; by autocatalysis (By

Alternative splicing; ATP-binding; Complete proteome; Cytoplasm; Disulfide bond; Kinase; Nucleotide-binding; Phosphoprotein; Polymorphism; Protein synthesis inhibitor; Reference proteome; Repeat; Serine/threonine-protein kinase; Transferase.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:UniProtKB.
GO:0020037; F:heme binding; ISS:UniProtKB.
GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
GO:0008285; P:negative regulation of cell proliferation; IEA:Compara.
GO:0046986; P:negative regulation of hemoglobin biosynthetic process; ISS:UniProtKB.
GO:0045993; P:negative regulation of translational initiation by iron; NAS:UniProtKB.
GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
GO:0046501; P:protoporphyrinogen IX metabolic process; IEA:Compara.
GO:0010999; P:regulation of eIF2 alpha phosphorylation by heme; IEA:Compara.
GO:0009605; P:response to external stimulus; IEP:UniProtKB.
GO:0006950; P:response to stress; IEP:UniProtKB.

IPR015516; Haem-reg_EIF2A_Kinase.
IPR011009; Kinase-like_dom.
IPR000719; Prot_kinase_cat_dom.
IPR017441; Protein_kinase_ATP_BS.
IPR008271; Ser/Thr_kinase_AS.

PS00107; PROTEIN_KINASE_ATP
PS50011; PROTEIN_KINASE_DOM
PS00108; PROTEIN_KINASE_ST