UniProt Accession

 E2AK1_HUMAN; Q9BQI3; A8K2R2; Q549K6; Q8NBW3; Q9HC02; Q9NYE0; Q9P0V6; Q9P1J5; Q9P2H8; Q9UHG4 

Genbank Protein ID

 AF255050; AF100784; AF181071; AB037790; AF183414; AL136563; AF147094; AK075192; AK290327; AL834494; CH236963; CH878731; BC006524; AF116634 

Genbank Nucleotide ID

 AAF70289.1; AAP97223.1; AAF18391.1; BAA92607.1; AAG09683.1; CAB66498.1; AAF66736.1; BAC11461.1; BAF83016.1; CAD39152.1; EAL23714.1; EAW55049.1; AAH06524.1; AAF71057.1 

Protein Name

 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 

Gene Name

 EIF2AK1 

Gene Synonyms/Alias

 HRI; KIAA1369; PRO1362 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
10	GGNSGVRKREEEGDG	ubiquitination	[1]
175	EELAILGKGGYGRVY	ubiquitination	[1, 2]
303	DTENQNNKSVKYTTN	ubiquitination	[1, 2]
472	ACTDILQKNTDWTNR	ubiquitination	[2]
558	KRCPVQAKYIQHLTR	ubiquitination	[2]
609	KEIAELKKQLNLLSQ	ubiquitination	[2]

Reference

 [1] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961] 

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). 

Sequence Annotation

 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  

Keyword

 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. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 630 AA 

Protein Sequence

Gene Ontology

 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. 

Interpro

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

Pfam

 PF00069; Pkinase 

SMART

  

PROSITE

 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS