Q9NZJ5 · E2AK3_HUMAN
- ProteinEukaryotic translation initiation factor 2-alpha kinase 3
- GeneEIF2AK3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1116 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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).
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).
Catalytic activity
- L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+This reaction proceeds in the forward direction.
Activity regulation
Inhibited by HSPA5/BIP in absence of stress (PubMed:11907036).
Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in trans-autophosphorylation and kinase activity induction (PubMed:11907036).
Inactivated following phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) (By similarity).
Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress (PubMed:39116259).
Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in trans-autophosphorylation and kinase activity induction (PubMed:11907036).
Inactivated following phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) (By similarity).
Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress (PubMed:39116259).
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Binding site | 599-607 | ATP (UniProtKB | ChEBI) | |||
Binding site | 622 | ATP (UniProtKB | ChEBI) | |||
Active site | 937 | Proton acceptor | |||
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameEukaryotic translation initiation factor 2-alpha kinase 3
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9NZJ5
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Single-pass type I membrane protein
Note: Localizes to the Localizes to endoplasmic reticulum membrane (By similarity).
Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (PubMed:39116259).
Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (PubMed:39116259).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Topological domain | 30-514 | Lumenal | |||
Transmembrane | 515-535 | Helical | |||
Topological domain | 536-1116 | Cytoplasmic | |||
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Wolcott-Rallison syndrome (WRS)
- Note
- DescriptionA rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, intellectual disability and cardiovascular abnormalities.
- See alsoMIM:226980
Natural variants in WRS
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_089927 | 69-1116 | missing | in WRS | |
VAR_089928 | 332-1116 | missing | in WRS | |
VAR_089929 | 334-1116 | missing | in WRS | |
VAR_011408 | 588 | R>Q | in WRS; dbSNP:rs121908569 | |
VAR_089930 | 658 | W>S | in WRS; uncertain significance | |
VAR_089931 | 878 | S>P | in WRS; decreased ability to phosphorylate EIF2S1/eIF-2-alpha | |
VAR_089932 | 903-1116 | missing | in WRS; uncertain significance | |
VAR_089933 | 940 | P>S | in WRS; uncertain significance | |
VAR_089934 | 994 | E>Q | in WRS; uncertain significance | |
VAR_089935 | 1065-1116 | missing | in WRS |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Natural variant | VAR_089927 | 69-1116 | in WRS | ||
Natural variant | VAR_011409 | 136 | in dbSNP:rs867529 | ||
Mutagenesis | 164 | Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha. | |||
Natural variant | VAR_011410 | 166 | in dbSNP:rs13045 | ||
Natural variant | VAR_089928 | 332-1116 | in WRS | ||
Natural variant | VAR_089929 | 334-1116 | in WRS | ||
Mutagenesis | 388 | Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha. | |||
Mutagenesis | 395 | Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha. | |||
Mutagenesis | 397 | Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha. | |||
Natural variant | VAR_040477 | 566 | in dbSNP:rs55791823 | ||
Natural variant | VAR_011408 | 588 | in WRS; dbSNP:rs121908569 | ||
Natural variant | VAR_089930 | 658 | in WRS; uncertain significance | ||
Natural variant | VAR_011411 | 704 | in dbSNP:rs1805165 | ||
Natural variant | VAR_040478 | 716 | in dbSNP:rs55861585 | ||
Natural variant | VAR_089931 | 878 | in WRS; decreased ability to phosphorylate EIF2S1/eIF-2-alpha | ||
Natural variant | VAR_089932 | 903-1116 | in WRS; uncertain significance | ||
Natural variant | VAR_089933 | 940 | in WRS; uncertain significance | ||
Natural variant | VAR_089934 | 994 | in WRS; uncertain significance | ||
Natural variant | VAR_089935 | 1065-1116 | in WRS | ||
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 1,218 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, glycosylation, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | ||
---|---|---|---|---|---|---|
Signal | 1-29 | UniProt | ||||
Chain | PRO_0000024322 | 30-1116 | UniProt | Eukaryotic translation initiation factor 2-alpha kinase 3 | ||
Glycosylation | 258 | UniProt | N-linked (GlcNAc...) asparagine | |||
Modified residue (large scale data) | 555 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 561 | PRIDE | Phosphothreonine | |||
Modified residue (large scale data) | 567 | PRIDE | Phosphoserine | |||
Modified residue | 619 | UniProt | Phosphotyrosine; by autocatalysis | |||
Modified residue (large scale data) | 685 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 686 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 688 | PRIDE | Phosphoserine | |||
Modified residue | 715 | UniProt | Phosphoserine | |||
Modified residue (large scale data) | 715 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 719 | PRIDE | Phosphoserine | |||
Modified residue | 802 | UniProt | Phosphothreonine | |||
Modified residue (large scale data) | 844 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 845 | PRIDE | Phosphoserine | |||
Modified residue | 982 | UniProt | Phosphothreonine | |||
Modified residue | 1094 | UniProt | Phosphoserine | |||
Modified residue (large scale data) | 1094 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 1096 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 1106 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 1109 | PRIDE | Phosphoserine | |||
Modified residue (large scale data) | 1111 | PRIDE | Phosphoserine | |||
Post-translational modification
Oligomerization of the N-terminal ER luminal domain by ER stress promotes EIF2AK3/PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity).
Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity (PubMed:22169477).
Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity (PubMed:22169477).
Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (By similarity).
Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity (PubMed:22169477).
Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity (PubMed:22169477).
Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (By similarity).
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Ubiquitous. A high level expression is seen in secretory tissues.
Induction
By endoplasmic reticulum stress.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Forms dimers with HSPA5/BIP in resting cells (PubMed:11907036).
Homotetramerizes in response to endoplasmic reticulum (ER) stress, leading to its activation (PubMed:25925385).
Interacts with HSP90B1/GRP94 (PubMed:11907036).
Interacts with DNAJC3; inhibiting EIF2AK3/PERK activity (By similarity).
Interacts with ATAD3A; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha (PubMed:39116259).
Interacts with MFN2 (By similarity).
Interacts with TMEM33 (PubMed:26268696).
Interacts with PDIA6 (PubMed:24508390).
Interacts with LACC1 (PubMed:31875558).
Homotetramerizes in response to endoplasmic reticulum (ER) stress, leading to its activation (PubMed:25925385).
Interacts with HSP90B1/GRP94 (PubMed:11907036).
Interacts with DNAJC3; inhibiting EIF2AK3/PERK activity (By similarity).
Interacts with ATAD3A; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha (PubMed:39116259).
Interacts with MFN2 (By similarity).
Interacts with TMEM33 (PubMed:26268696).
Interacts with PDIA6 (PubMed:24508390).
Interacts with LACC1 (PubMed:31875558).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | IntAct | |
---|---|---|---|---|---|
BINARY | Q9NZJ5 | EIF2AK3 Q9NZJ5 | 2 | EBI-766076, EBI-766076 | |
BINARY | Q9NZJ5 | HSPA5 P11021 | 4 | EBI-766076, EBI-354921 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias, domain.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Region | 77-101 | Disordered | |||
Compositional bias | 87-101 | Basic and acidic residues | |||
Region | 550-571 | Disordered | |||
Domain | 593-1077 | Protein kinase | |||
Region | 647-888 | Insert loop | |||
Region | 841-863 | Disordered | |||
Region | 1090-1116 | Disordered | |||
Domain
The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.
The insert loop specifically recongnizes and binds EIF2S1/eIF-2-alpha.
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length1,116
- Mass (Da)125,216
- Last updated2010-05-18 v3
- MD5 ChecksumA1CF86ECF6D850F68C026C5587994C17
Computationally mapped potential isoform sequences
There are 8 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A804HI66 | A0A804HI66_HUMAN | EIF2AK3 | 17 | ||
A0A494BZR8 | A0A494BZR8_HUMAN | EIF2AK3 | 225 | ||
A0A804HIT4 | A0A804HIT4_HUMAN | EIF2AK3 | 965 | ||
A0A804HJ50 | A0A804HJ50_HUMAN | EIF2AK3 | 859 | ||
A0A804HLC2 | A0A804HLC2_HUMAN | EIF2AK3 | 177 | ||
A0A804HJV6 | A0A804HJV6_HUMAN | EIF2AK3 | 79 | ||
A0A804HL08 | A0A804HL08_HUMAN | EIF2AK3 | 139 | ||
A0A494C186 | A0A494C186_HUMAN | EIF2AK3 | 63 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Sequence conflict | 14 | in Ref. 1; AAD19961, 2; AAF61199, 3; AAF91480, 4; BAG37696 and 6; AAI26357 | |||
Compositional bias | 87-101 | Basic and acidic residues | |||
Sequence conflict | 490 | in Ref. 2; AAF61199 | |||
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF110146 EMBL· GenBank· DDBJ | AAD19961.1 EMBL· GenBank· DDBJ | mRNA | ||
AF193339 EMBL· GenBank· DDBJ | AAF61199.1 EMBL· GenBank· DDBJ | mRNA | ||
AF284615 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284604 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284605 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284606 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284607 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284608 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284609 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284610 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284611 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284612 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284613 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF284614 EMBL· GenBank· DDBJ | AAF91480.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK315287 EMBL· GenBank· DDBJ | BAG37696.1 EMBL· GenBank· DDBJ | mRNA | ||
AC062029 EMBL· GenBank· DDBJ | AAY14777.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AC104134 EMBL· GenBank· DDBJ | AAY24331.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC126354 EMBL· GenBank· DDBJ | AAI26355.1 EMBL· GenBank· DDBJ | mRNA | ||
BC126356 EMBL· GenBank· DDBJ | AAI26357.1 EMBL· GenBank· DDBJ | mRNA |