EIF2AK3

Chr 2p11.2

eukaryotic translation initiation factor 2 alpha kinase 3

Aliases:: PEK, PERK
MANE:: ENST00000303236.9

OMIM: 604032 ↗NCBI: 9451 ↗Ensembl ↗

Annotations refreshed 1 month ago.

Predicted protein structure

AlphaFold predicted structure

EIF2AK3 · Q9NZJ5

v62025-08-01

Predicted Aligned Error matrix for EIF2AK3 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

59.1/ 100

Low

1,116 residues

Confidence breakdown

Very high(≥ 90)16%
Confident(70–90)26%
Low(50–70)12%
Very low(< 50)47%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

DDG2P
BIALLELIC, autosomal or pseudoautosomal
Diabetes with additional phenotypes suggestive of a monogenic aetiology
BIALLELIC, autosomal or pseudoautosomal
Familial diabetes
BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies
BIALLELIC, autosomal or pseudoautosomal
Intellectual disability
BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes
BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia
BIALLELIC, autosomal or pseudoautosomal
Multiple Epiphyseal Dysplasia
BIALLELIC, autosomal or pseudoautosomal

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Disease associations (Open Targets)

Wolcott-Rallison syndrome
0.82
cancer
0.53
neurodegenerative disease
0.47
Menkes disease
0.34
progressive supranuclear palsy
0.31
uterine corpus leiomyoma
0.28
sialolithiasis
0.26
autoimmune disorder of central nervous system
0.24
hereditary disease
0.20
liver disorder
0.19

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

Eukaryotic translation initiation factor 2-alpha kinase 3

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, such as unfolded protein response (UPR) (PubMed:10026192, PubMed:10677345, PubMed:11907036, PubMed:12086964, PubMed:25925385, PubMed:31023583). Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation (PubMed:10677345, PubMed:27917829, PubMed:31023583). 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 activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:10026192, PubMed:10677345, PubMed:31023583, PubMed:33384352). The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes (PubMed:31023583). In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites (PubMed:39116259). In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2 (By similarity). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Involved in control of mitochondrial morphology and function (By similarity)