Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

EIF2AK1 (Q9BQI3) - Overview - Molecular Target Synopsis

Protein


EIF2AK1, Eukaryotic translation initiation factor 2-alpha kinase 1
Enzyme Classification 2.7.11.1
UniProt Q9BQI3

Also Known as E2AK1_HUMAN, EIF2AK1, HRI, KIAA1369

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. Synthesized in an inactive form that binds to the N-terminal domain of CDC37. Has to be associated with a multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation and activation by autophosphorylation. The phosphatase PPP5C modulates this activation. Forms oligomers. Has been reported as a non-covalently bound homodimer, as well as a hexamer in the absence of hemin. Converted to an inactive disulfide linked homodimer in the presence of hemin.

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: EIF2AK1 is active in the following subcellular-locations: cytoplasm.
GO terms: EIF2AK1 is active in the following subcellular-locations: cytoplasm.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project EIF2AK1 has gain in 5 cell-lines, loss in 1 cell-lines and no signal in 999 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: U251, SR, 786_0

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H596, NCI-H209, BICR 31

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, SK-N-SH, HSMM

(see details)

RNA Interference


EIF2AK1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: 93VU, H1650. (see details)

3D Structures


At greater than 35% identity similarity to EIF2AK1 there are:
15 structures (26 chains) solved
11 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


EIF2AK1 has been screened with 181 compounds (268 bioactivities), 18 compounds have bioactivities that show binding affinity of <= 500nM (18 bioactivities). (see details)