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

ERN1 (O75460) - Overview - Molecular Target Synopsis

Protein


ERN1, Serine/threonine-protein kinase/endoribonuclease IRE1
Enzyme Classification 2.7.11.1
UniProt O75460

Also Known as ERN1_HUMAN, ERN1, IRE1

Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875). 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 protein 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:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). 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). Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). 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).

6HX1
IRE1 ALPHA IN COMPLEX WITH IMIDAZO[1,2-B]PYRIDAZIN-8-AMINE COMPOUND 2
RCSB/PDB
Inspect Structure
See all 3D Structures for ERN1

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
977ENSG00000178607ENST00000433197ENSP00000401445O75460-1
334ENSG00000178607ENST00000606895ENSP00000475519
70O75460-2

Sub-cellular localization


UniProt: ERN1 is active in the following subcellular-locations: endoplasmic reticulum membrane.
GO terms: ERN1 is active in the following subcellular-locations: AIP1-IRE1 complex, cytoplasm, endoplasmic reticulum, endoplasmic reticulum membrane, integral component of endoplasmic reticulum membrane, Ire1 complex, IRE1-RACK1-PP2A complex, IRE1-TRAF2-ASK1 complex, mitochondrion, nuclear inner membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project ERN1 has gain in 5 cell-lines, loss in 0 cell-lines and no signal in 1000 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: RPMI_8226, LOXIMVI, HS578T

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SK-MM-2, A3/KAW, Hs 746T

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, IMR-90, HMEC

(see details)

RNA Interference


ERN1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: G292, MHM. (see details)

3D Structures


For ERN1 there are:
11 structures (21 chains) solved
8 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


ERN1 has been screened with 435 compounds (660 bioactivities), 177 compounds have bioactivities that show binding affinity of <= 500nM (196 bioactivities). (see details)