O75460 · ERN1_HUMAN
- ProteinSerine/threonine-protein kinase/endoribonuclease IRE1
- GeneERN1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids977 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875).
Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875).
The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:21317875, PubMed:24508390).
The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:21317875, PubMed:24508390).
Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262).
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Cofactor
Activity regulation
Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683).
Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA) (By similarity).
Features
Showing features for binding site, active site, site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 577-585 | ATP (UniProtKB | ChEBI) | ||||
Sequence: LGHGAEGTI | ||||||
Binding site | 599 | ATP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 643-645 | ATP (UniProtKB | ChEBI) | ||||
Sequence: ELC | ||||||
Active site | 688 | Proton acceptor | ||||
Sequence: D | ||||||
Binding site | 690-693 | ATP (UniProtKB | ChEBI) | ||||
Sequence: KPHN | ||||||
Binding site | 711 | ATP (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Site | 892 | Interacts with hydroxy-aryl-aldehyde inhibitors | ||||
Sequence: Y |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameSerine/threonine-protein kinase/endoribonuclease IRE1
- Alternative names
Including 2 domains:
- Recommended nameSerine/threonine-protein kinase
- EC number
- Recommended nameEndoribonuclease
- EC number
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO75460
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 19-443 | Lumenal | ||||
Sequence: IFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDPVLQVPTHVEEPAFLPDPNDGSLYTLGSKNNEGLTKLPFTIPELVQASPCRSSDGILYMGKKQDIWYVIDLLTGEKQQTLSSAFADSLCPSTSLLYLGRTEYTITMYDTKTRELRWNATYFDYAASLPEDDVDYKMSHFVSNGDGLVVTVDSESGDVLWIQNYASPVVAFYVWQREGLRKVMHINVAVETLRYLTFMSGEVGRITKWKYPFPKETEAKSKLTPTLYVGKYSTSLYASPSMVHEGVAVVPRGSTLPLLEGPQTDGVTIGDKGECVITPSTDVKFDPGLKSKNKLNYLRNYWLLIGHHETPLSASTKMLERFPNNLPKHRENVIPADSEKKSFEEVINLVDQTSENAPTTVSRDVEEKPAHAPARPEAPVDSMLKD | ||||||
Transmembrane | 444-464 | Helical | ||||
Sequence: MATIILSTFLLIGWVAFIITY | ||||||
Topological domain | 465-977 | Cytoplasmic | ||||
Sequence: PLSMHQQQQLQHQQFQKELEKIQLLQQQQQQLPFHPPGDTAQDGELLDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPSLEQDDGDEETSVVIVGKISFCPKDVLGHGAEGTIVYRGMFDNRDVAVKRILPECFSFADREVQLLRESDEHPNVIRYFCTEKDRQFQYIAIELCAATLQEYVEQKDFAHLGLEPITLLQQTTSGLAHLHSLNIVHRDLKPHNILISMPNAHGKIKAMISDFGLCKKLAVGRHSFSRRSGVPGTEGWIAPEMLSEDCKENPTYTVDIFSAGCVFYYVISEGSHPFGKSLQRQANILLGACSLDCLHPEKHEDVIARELIEKMIAMDPQKRPSAKHVLKHPFFWSLEKQLQFFQDVSDRIEKESLDGPIVKQLERGGRAVVKMDWRENITVPLQTDLRKFRTYKGGSVRDLLRAMRNKKHHYRELPAEVRETLGSLPDDFVCYFTSRFPHLLAHTYRAMELCSHERLFQPYYFHEPPEPQPPVTPDAL |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 105 | Impaired ability to homodimerize. | ||||
Sequence: Q → E | ||||||
Mutagenesis | 109 | No effect on dimerization. No effect on interaction with P4HB; when associated with S-148 and S-332. | ||||
Sequence: C → S | ||||||
Mutagenesis | 123 | Abolishes ability to homodimerize. | ||||
Sequence: D → P | ||||||
Mutagenesis | 125 | Abolishes ability to homodimerize. | ||||
Sequence: W → A | ||||||
Mutagenesis | 148 | No effect on dimerization. Weakens dimer; when associated with S-332. Abolishes interaction with PDIA6. Prolonged splicing of XBP1, probably due to prolonged activation of PDIA6. Inhibits formation of oxidized multimeric forms of ERN1 in response to ER stress. No effect on interaction with P4HB; when associated with S-109 and S-332. | ||||
Sequence: C → S | ||||||
Natural variant | VAR_040488 | 244 | in a renal clear cell carcinoma sample; somatic mutation; dbSNP:rs1397145500 | |||
Sequence: N → S | ||||||
Mutagenesis | 332 | No effect on dimerization. Weakens dimer; when associated with S-148. No effect on interaction with P4HB; when associated with S-109 and S-148. | ||||
Sequence: C → S | ||||||
Natural variant | VAR_040489 | 418 | in dbSNP:rs55869215 | |||
Sequence: V → M | ||||||
Natural variant | VAR_040490 | 474 | in a lung adenocarcinoma sample; somatic mutation; dbSNP:rs186305118 | |||
Sequence: L → R | ||||||
Mutagenesis | 599 | Loss of autophosphorylation and of endoribonuclease activity. Inhibition of growth arrest. | ||||
Sequence: K → A | ||||||
Natural variant | VAR_040491 | 635 | in a gastric adenocarcinoma sample; somatic mutation; dbSNP:rs146710304 | |||
Sequence: R → W | ||||||
Natural variant | VAR_040492 | 700 | in dbSNP:rs918253870 | |||
Sequence: N → S | ||||||
Natural variant | VAR_040493 | 769 | in a glioblastoma multiforme sample; somatic mutation | |||
Sequence: S → F | ||||||
Natural variant | VAR_040494 | 830 | in an ovarian serous carcinoma sample; somatic mutation; dbSNP:rs1279653488 | |||
Sequence: P → L |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 933 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, glycosylation, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Signal | 1-18 | UniProt | |||||
Sequence: MPARRLLLLLTLLLPGLG | |||||||
Chain | PRO_0000024327 | 19-977 | UniProt | Serine/threonine-protein kinase/endoribonuclease IRE1 | |||
Sequence: IFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDPVLQVPTHVEEPAFLPDPNDGSLYTLGSKNNEGLTKLPFTIPELVQASPCRSSDGILYMGKKQDIWYVIDLLTGEKQQTLSSAFADSLCPSTSLLYLGRTEYTITMYDTKTRELRWNATYFDYAASLPEDDVDYKMSHFVSNGDGLVVTVDSESGDVLWIQNYASPVVAFYVWQREGLRKVMHINVAVETLRYLTFMSGEVGRITKWKYPFPKETEAKSKLTPTLYVGKYSTSLYASPSMVHEGVAVVPRGSTLPLLEGPQTDGVTIGDKGECVITPSTDVKFDPGLKSKNKLNYLRNYWLLIGHHETPLSASTKMLERFPNNLPKHRENVIPADSEKKSFEEVINLVDQTSENAPTTVSRDVEEKPAHAPARPEAPVDSMLKDMATIILSTFLLIGWVAFIITYPLSMHQQQQLQHQQFQKELEKIQLLQQQQQQLPFHPPGDTAQDGELLDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPSLEQDDGDEETSVVIVGKISFCPKDVLGHGAEGTIVYRGMFDNRDVAVKRILPECFSFADREVQLLRESDEHPNVIRYFCTEKDRQFQYIAIELCAATLQEYVEQKDFAHLGLEPITLLQQTTSGLAHLHSLNIVHRDLKPHNILISMPNAHGKIKAMISDFGLCKKLAVGRHSFSRRSGVPGTEGWIAPEMLSEDCKENPTYTVDIFSAGCVFYYVISEGSHPFGKSLQRQANILLGACSLDCLHPEKHEDVIARELIEKMIAMDPQKRPSAKHVLKHPFFWSLEKQLQFFQDVSDRIEKESLDGPIVKQLERGGRAVVKMDWRENITVPLQTDLRKFRTYKGGSVRDLLRAMRNKKHHYRELPAEVRETLGSLPDDFVCYFTSRFPHLLAHTYRAMELCSHERLFQPYYFHEPPEPQPPVTPDAL | |||||||
Glycosylation | 176 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Modified residue | 724 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 724 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 729 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 973 | UniProt | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
In response to ER stress, phosphorylated at Ser-724, Ser-729 and possibly Ser-726; phosphorylation promotes oligomerization and endoribonuclease activity (PubMed:30118681).
Dephosphorylated at Ser-724, Ser-729 and possibly Ser-726 by RPAP2 to abort failed ER-stress adaptation and trigger apoptosis (PubMed:30118681).
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:16973740, PubMed:21317875, PubMed:24508390, PubMed:30118681).
Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535).
Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525).
Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525).
Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390).
Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity).
Interacts with TAOK3 and TRAF2 (PubMed:11278723).
Interacts with RNF13 (PubMed:23378536).
Interacts with LACC1 (PubMed:31875558).
Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204).
Interacts (via N-terminus) with P4HB/PDIA1; the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (PubMed:32149426).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 410-434 | Disordered | ||||
Sequence: TSENAPTTVSRDVEEKPAHAPARPE | ||||||
Region | 491-559 | Disordered | ||||
Sequence: QQQQQLPFHPPGDTAQDGELLDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPSLEQDDGDE | ||||||
Compositional bias | 511-551 | Polar residues | ||||
Sequence: LDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPS | ||||||
Domain | 571-832 | Protein kinase | ||||
Sequence: FCPKDVLGHGAEGTIVYRGMFDNRDVAVKRILPECFSFADREVQLLRESDEHPNVIRYFCTEKDRQFQYIAIELCAATLQEYVEQKDFAHLGLEPITLLQQTTSGLAHLHSLNIVHRDLKPHNILISMPNAHGKIKAMISDFGLCKKLAVGRHSFSRRSGVPGTEGWIAPEMLSEDCKENPTYTVDIFSAGCVFYYVISEGSHPFGKSLQRQANILLGACSLDCLHPEKHEDVIARELIEKMIAMDPQKRPSAKHVLKHPFF | ||||||
Domain | 835-963 | KEN | ||||
Sequence: LEKQLQFFQDVSDRIEKESLDGPIVKQLERGGRAVVKMDWRENITVPLQTDLRKFRTYKGGSVRDLLRAMRNKKHHYRELPAEVRETLGSLPDDFVCYFTSRFPHLLAHTYRAMELCSHERLFQPYYFH | ||||||
Region | 906-907 | Interacts with hydroxy-aryl-aldehyde inhibitors | ||||
Sequence: NK |
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
This entry describes 2 isoforms produced by Alternative splicing.
O75460-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length977
- Mass (Da)109,735
- Last updated2008-07-01 v2
- ChecksumA2DF808CCE015536
O75460-2
- Name2
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A7P0TA38 | A0A7P0TA38_HUMAN | ERN1 | 96 | ||
A0A7P0TAB0 | A0A7P0TAB0_HUMAN | ERN1 | 905 |
Features
Showing features for alternative sequence, sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_034582 | 19-70 | in isoform 2 | |||
Sequence: IFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDPVLQVPTHVEE → VSDRGAWGGGQLATAGSGPGQRRGAGAGVRAGSATAAARCPVSPAVGGSGRA | ||||||
Alternative sequence | VSP_034583 | 71-977 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 190-191 | in Ref. 1; AAC25991 | ||||
Sequence: DV → EG | ||||||
Compositional bias | 511-551 | Polar residues | ||||
Sequence: LDTSGPYSESSGTSSPSTSPRASNHSLCSGSSASKAGSSPS | ||||||
Sequence conflict | 768 | in Ref. 1; AAC25991 | ||||
Sequence: I → V | ||||||
Sequence conflict | 816 | in Ref. 2; BAF85092 | ||||
Sequence: D → G | ||||||
Sequence conflict | 824-825 | in Ref. 1; AAC25991 | ||||
Sequence: KH → ND | ||||||
Sequence conflict | 880 | in Ref. 1; AAC25991 | ||||
Sequence: V → D | ||||||
Sequence conflict | 904 | in Ref. 2; BAF85092 | ||||
Sequence: M → T | ||||||
Sequence conflict | 924 | in Ref. 1; AAC25991 | ||||
Sequence: S → T |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF059198 EMBL· GenBank· DDBJ | AAC25991.1 EMBL· GenBank· DDBJ | mRNA | ||
AK292403 EMBL· GenBank· DDBJ | BAF85092.1 EMBL· GenBank· DDBJ | mRNA | ||
DA254477 EMBL· GenBank· DDBJ | - | mRNA | No translation available. | |
AB209869 EMBL· GenBank· DDBJ | BAD93106.1 EMBL· GenBank· DDBJ | mRNA | ||
AC005803 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AC025362 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471109 EMBL· GenBank· DDBJ | EAW94214.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC130405 EMBL· GenBank· DDBJ | AAI30406.1 EMBL· GenBank· DDBJ | mRNA | ||
BC130407 EMBL· GenBank· DDBJ | AAI30408.1 EMBL· GenBank· DDBJ | mRNA | ||
BI912495 EMBL· GenBank· DDBJ | - | mRNA | No translation available. |