InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Eif2ak1

Summary

InnateDB Protein

IDBP-207906.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Eif2ak1

Protein Name

eukaryotic translation initiation factor 2 alpha kinase 1

Synonyms

HCR; Hri;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000098056

InnateDB Gene

IDBG-207904 (Eif2ak1)

Protein Structure

UniProt Annotation

Function

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. {ECO:0000269PubMed:11726526, ECO:0000269PubMed:16893190, ECO:0000269PubMed:20071449}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:17932563}.

Disease Associations

Note=Defects in Eif2ak1 are a cause of hyperchromic anemia in animals suffering from iron deficiency. The number of red blood cells is decreased due to increased apoptosis of erythroid precursor cells, probably because globins misfold and aggregate in the absence of heme.

Tissue Specificity

Expressed predominantly in erythroid cells, mature reticulocytes, as well as fetal liver nucleated erythroid cells. At much lower levels, expressed in hepatocytes and bone marrow-derived macrophages (at protein level). {ECO:0000269PubMed:11689689, ECO:0000269PubMed:17932563, ECO:0000269PubMed:20071449}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 5 experimentally validated interaction(s) in this database.
They are also associated with 6 interaction(s) predicted by orthology.

Experimentally validated
Total	5 [view]
Protein-Protein	5 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	6 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004694	eukaryotic translation initiation factor 2alpha kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0020037	heme binding
GO:0042803	protein homodimerization activity

Biological Process

GO:0006417	regulation of translation
GO:0006468	protein phosphorylation
GO:0006950	response to stress
GO:0008285	negative regulation of cell proliferation
GO:0009605	response to external stimulus
GO:0010999	regulation of eIF2 alpha phosphorylation by heme
GO:0017148	negative regulation of translation
GO:0046501	protoporphyrinogen IX metabolic process
GO:0046777	protein autophosphorylation
GO:0046984	regulation of hemoglobin biosynthetic process
GO:0046986	negative regulation of hemoglobin biosynthetic process

Cellular Component

GO:0005737

cytoplasm

Protein Structure and Domains

PDB ID

MGI:1353448

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine- /dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt