ERN1_HUMAN
ID ERN1_HUMAN Reviewed; 977 AA.
AC O75460; A1L457; A8K8N8; A8MXS7; Q59EE2;
DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-2008, sequence version 2.
DT 03-AUG-2022, entry version 209.
DE RecName: Full=Serine/threonine-protein kinase/endoribonuclease IRE1 {ECO:0000305};
DE AltName: Full=Endoplasmic reticulum-to-nucleus signaling 1 {ECO:0000303|PubMed:9637683};
DE AltName: Full=Inositol-requiring protein 1 {ECO:0000303|PubMed:9637683};
DE Short=hIRE1p {ECO:0000303|PubMed:9637683};
DE AltName: Full=Ire1-alpha {ECO:0000303|PubMed:11779464};
DE Short=IRE1a {ECO:0000303|PubMed:11779464};
DE Includes:
DE RecName: Full=Serine/threonine-protein kinase;
DE EC=2.7.11.1 {ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};
DE Includes:
DE RecName: Full=Endoribonuclease;
DE EC=3.1.26.- {ECO:0000269|PubMed:21317875};
DE Flags: Precursor;
GN Name=ERN1 {ECO:0000312|HGNC:HGNC:3449};
GN Synonyms=IRE1 {ECO:0000312|EMBL:AAC25991.1};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAC25991.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, ACTIVITY REGULATION,
RP COFACTOR, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AUTOPHOSPHORYLATION,
RP GLYCOSYLATION, AND MUTAGENESIS OF LYS-599.
RC TISSUE=Liver {ECO:0000312|EMBL:AAC25991.1};
RX PubMed=9637683; DOI=10.1101/gad.12.12.1812;
RA Tirasophon W., Welihinda A.A., Kaufman R.J.;
RT "A stress response pathway from the endoplasmic reticulum to the nucleus
RT requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in
RT mammalian cells.";
RL Genes Dev. 12:1812-1824(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Endothelial cell;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 2-977 (ISOFORM 2).
RC TISSUE=Brain, and Leukocyte;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION.
RX PubMed=11779464; DOI=10.1016/s0092-8674(01)00611-0;
RA Yoshida H., Matsui T., Yamamoto A., Okada T., Mori K.;
RT "XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress
RT to produce a highly active transcription factor.";
RL Cell 107:881-891(2001).
RN [8]
RP INTERACTION WITH TAOK3 AND TRAF2.
RX PubMed=11278723; DOI=10.1074/jbc.m010677200;
RA Yoneda T., Imaizumi K., Oono K., Yui D., Gomi F., Katayama T., Tohyama M.;
RT "Activation of caspase-12, an endoplastic reticulum (ER) resident caspase,
RT through tumor necrosis factor receptor-associated factor 2-dependent
RT mechanism in response to the ER stress.";
RL J. Biol. Chem. 276:13935-13940(2001).
RN [9] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF LYS-599.
RX PubMed=11175748; DOI=10.1038/35055065;
RA Iwawaki T., Hosoda A., Okuda T., Kamigori Y., Nomura-Furuwatari C.,
RA Kimata Y., Tsuru A., Kohno K.;
RT "Translational control by the ER transmembrane kinase/ribonuclease IRE1
RT under ER stress.";
RL Nat. Cell Biol. 3:158-164(2001).
RN [10] {ECO:0000305}
RP FUNCTION, HOMODIMERIZATION, ACTIVITY REGULATION, INTERACTION WITH HSPA5,
RP AND MUTAGENESIS OF CYS-109; CYS-148 AND CYS-332.
RX PubMed=12637535; DOI=10.1074/jbc.m300418200;
RA Liu C.Y., Xu Z., Kaufman R.J.;
RT "Structure and intermolecular interactions of the luminal dimerization
RT domain of human IRE1alpha.";
RL J. Biol. Chem. 278:17680-17687(2003).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-973, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP ADP-RIBOSYLATION BY PARP16.
RX PubMed=23103912; DOI=10.1038/ncb2593;
RA Jwa M., Chang P.;
RT "PARP16 is a tail-anchored endoplasmic reticulum protein required for the
RT PERK-and IRE1alpha-mediated unfolded protein response.";
RL Nat. Cell Biol. 14:1223-1230(2012).
RN [14]
RP SUBUNIT, AND INTERACTION WITH DNAJB9 AND HSPA5.
RX PubMed=29198525; DOI=10.1016/j.cell.2017.10.040;
RA Amin-Wetzel N., Saunders R.A., Kamphuis M.J., Rato C., Preissler S.,
RA Harding H.P., Ron D.;
RT "A J-Protein co-chaperone recruits bip to monomerize IRE1 and repress the
RT unfolded protein response.";
RL Cell 171:1625-1637(2017).
RN [15]
RP INTERACTION WITH RNF13.
RX PubMed=23378536; DOI=10.1074/jbc.m112.368829;
RA Arshad M., Ye Z., Gu X., Wong C.K., Liu Y., Li D., Zhou L., Zhang Y.,
RA Bay W.P., Yu V.C., Li P.;
RT "RNF13, a RING finger protein, mediates endoplasmic reticulum stress-
RT induced apoptosis through the inositol-requiring enzyme (IRE1alpha)/c-Jun
RT NH2-terminal kinase pathway.";
RL J. Biol. Chem. 288:8726-8736(2013).
RN [16]
RP INTERACTION WITH LACC1.
RX PubMed=31875558; DOI=10.1016/j.celrep.2019.11.105;
RA Huang C., Hedl M., Ranjan K., Abraham C.;
RT "LACC1 required for NOD2-induced, ER stress-mediated innate immune outcomes
RT in human macrophages and LACC1 risk variants modulate these outcomes.";
RL Cell Rep. 29:4525-4539(2019).
RN [17] {ECO:0007744|PDB:2HZ6}
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 24-390, SUBUNIT, AND MUTAGENESIS
RP OF GLN-105; ASP-123 AND TRP-125.
RX PubMed=16973740; DOI=10.1073/pnas.0606480103;
RA Zhou J., Liu C.Y., Back S.H., Clark R.L., Peisach D., Xu Z., Kaufman R.J.;
RT "The crystal structure of human IRE1 luminal domain reveals a conserved
RT dimerization interface required for activation of the unfolded protein
RT response.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:14343-14348(2006).
RN [18] {ECO:0007744|PDB:3P23}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 547-977 IN COMPLEX WITH ADP,
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AUTOPHOSPHORYLATION, AND
RP COFACTOR.
RX PubMed=21317875; DOI=10.1038/emboj.2011.18;
RA Ali M.M., Bagratuni T., Davenport E.L., Nowak P.R., Silva-Santisteban M.C.,
RA Hardcastle A., McAndrews C., Rowlands M.G., Morgan G.J., Aherne W.,
RA Collins I., Davies F.E., Pearl L.H.;
RT "Structure of the Ire1 autophosphorylation complex and implications for the
RT unfolded protein response.";
RL EMBO J. 30:894-905(2011).
RN [19]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-244; MET-418; ARG-474; TRP-635;
RP SER-700; PHE-769 AND LEU-830.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [20]
RP FUNCTION.
RX PubMed=21884936; DOI=10.1016/j.cell.2011.07.021;
RA Gee H.Y., Noh S.H., Tang B.L., Kim K.H., Lee M.G.;
RT "Rescue of DeltaF508-CFTR trafficking via a GRASP-dependent unconventional
RT secretion pathway.";
RL Cell 146:746-760(2011).
RN [21]
RP FUNCTION, INTERACTION WITH PDIA6, SUBUNIT, AND MUTAGENESIS OF CYS-148.
RX PubMed=24508390; DOI=10.1016/j.molcel.2014.01.004;
RA Eletto D., Eletto D., Dersh D., Gidalevitz T., Argon Y.;
RT "Protein disulfide isomerase A6 controls the decay of IRE1alpha signaling
RT via disulfide-dependent association.";
RL Mol. Cell 53:562-576(2014).
RN [22]
RP FUNCTION, INTERACTION WITH DDRGK1, AND PHOSPHORYLATION.
RX PubMed=28128204; DOI=10.1038/ncomms14186;
RA Liu J., Wang Y., Song L., Zeng L., Yi W., Liu T., Chen H., Wang M., Ju Z.,
RA Cong Y.S.;
RT "A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via
RT regulation of IRE1alpha stability.";
RL Nat. Commun. 8:14186-14186(2017).
RN [23]
RP FUNCTION.
RX PubMed=28067262; DOI=10.1038/srep39887;
RA Piao H., Kim J., Noh S.H., Kweon H.S., Kim J.Y., Lee M.G.;
RT "Sec16A is critical for both conventional and unconventional secretion of
RT CFTR.";
RL Sci. Rep. 7:39887-39887(2017).
RN [24]
RP INTERACTION WITH P4HB, AND MUTAGENESIS OF CYS-109; CYS-148 AND CYS-332.
RX PubMed=32149426; DOI=10.15252/embj.2019103841;
RA Yu J., Li T., Liu Y., Wang X., Zhang J., Wang X., Shi G., Lou J., Wang L.,
RA Wang C.C., Wang L.;
RT "Phosphorylation switches protein disulfide isomerase activity to maintain
RT proteostasis and attenuate ER stress.";
RL EMBO J. 39:e103841-e103841(2020).
CC -!- FUNCTION: Serine/threonine-protein kinase and endoribonuclease that
CC acts as a key sensor for the endoplasmic reticulum unfolded protein
CC response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535,
CC PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells,
CC the endoplasmic reticulum luminal domain is maintained in its inactive
CC monomeric state by binding to the endoplasmic reticulum chaperone
CC HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the
CC endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal
CC domain to homodimerize, promoting autophosphorylation of the kinase
CC domain and subsequent activation of the endoribonuclease activity
CC (PubMed:21317875). The endoribonuclease activity is specific for XBP1
CC mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464,
CC PubMed:24508390, PubMed:21317875). The resulting spliced transcript of
CC XBP1 encodes a transcriptional activator protein that up-regulates
CC expression of UPR target genes (PubMed:11779464, PubMed:24508390,
CC PubMed:21317875). Acts as an upstream signal for ER stress-induced
CC GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of
CC CFTR to cell membrane by modulating the expression and localization of
CC SEC16A (PubMed:21884936, PubMed:28067262).
CC {ECO:0000269|PubMed:11175748, ECO:0000269|PubMed:11779464,
CC ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875,
CC ECO:0000269|PubMed:21884936, ECO:0000269|PubMed:28067262,
CC ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:9637683,
CC ECO:0000305|PubMed:24508390}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21317875,
CC ECO:0000269|PubMed:9637683};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683};
CC -!- ACTIVITY REGULATION: The kinase domain is activated by trans-
CC autophosphorylation following homodimerization (PubMed:12637535,
CC PubMed:9637683). Kinase activity is required for activation of the
CC endoribonuclease domain (PubMed:12637535, PubMed:9637683).
CC Endoribonuclease activity is specifically inhibited by hydroxy-aryl-
CC aldehydes (HAA) (By similarity). {ECO:0000250|UniProtKB:Q9EQY0,
CC ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:9637683}.
CC -!- SUBUNIT: Monomer (PubMed:29198525, PubMed:16973740). Homodimer;
CC disulfide-linked; homodimerization takes place in response to
CC endoplasmic reticulum stress and promotes activation of the kinase and
CC endoribonuclease activities (PubMed:12637535, PubMed:24508390,
CC PubMed:16973740, PubMed:21317875). Dimer formation is driven by
CC hydrophobic interactions within the N-terminal luminal domains and
CC stabilized by disulfide bridges (PubMed:12637535). Interacts (via the
CC luminal region) with DNAJB9/ERdj4; interaction takes place in
CC unstressed cells and promotes recruitment of HSPA5/BiP
CC (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP;
CC HSPA5/BiP is a negative regulator of the unfolded protein response
CC (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent
CC activation of the protein (PubMed:12637535, PubMed:29198525). Interacts
CC with PDIA6, a negative regulator of the UPR; the interaction is direct
CC and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP
CC (via PH domain); the interaction occurs in a endoplasmic reticulum
CC stress-induced dependent manner and is required for subsequent
CC recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3
CC and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536).
CC Interacts with LACC1 (PubMed:31875558). Interacts (when
CC unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and
CC takes place in response to endoplasmic reticulum stress, regulating
CC ERN1/IRE1-alpha stability (PubMed:28128204). Interacts (via N-terminus)
CC with P4HB/PDIA1; the interaction is enhanced by phosphorylation of P4HB
CC by FAM20C in response to endoplasmic reticulum stress and results in
CC attenuation of ERN1 activity (PubMed:32149426).
CC {ECO:0000250|UniProtKB:Q9EQY0, ECO:0000269|PubMed:11278723,
CC ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:16973740,
CC ECO:0000269|PubMed:23378536, ECO:0000269|PubMed:24508390,
CC ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:29198525,
CC ECO:0000269|PubMed:31875558, ECO:0000269|PubMed:32149426}.
CC -!- INTERACTION:
CC O75460; Q07812: BAX; NbExp=2; IntAct=EBI-371750, EBI-516580;
CC O75460; O75460: ERN1; NbExp=2; IntAct=EBI-371750, EBI-371750;
CC O75460; P11021: HSPA5; NbExp=3; IntAct=EBI-371750, EBI-354921;
CC O75460; Q86TM6: SYVN1; NbExp=2; IntAct=EBI-371750, EBI-947849;
CC O75460; Q9H2K8: TAOK3; NbExp=3; IntAct=EBI-371750, EBI-1384100;
CC O75460; Q12933: TRAF2; NbExp=3; IntAct=EBI-371750, EBI-355744;
CC O75460; Q969M3: YIPF5; NbExp=3; IntAct=EBI-371750, EBI-2124787;
CC O75460; O08734: Bak1; Xeno; NbExp=2; IntAct=EBI-371750, EBI-822441;
CC O75460; Q07813: Bax; Xeno; NbExp=2; IntAct=EBI-371750, EBI-700711;
CC O75460; P20029: Hspa5; Xeno; NbExp=2; IntAct=EBI-371750, EBI-772325;
CC O75460-1; O75460-1: ERN1; NbExp=5; IntAct=EBI-15600828, EBI-15600828;
CC O75460-1; P11021: HSPA5; NbExp=4; IntAct=EBI-15600828, EBI-354921;
CC O75460-1; Q13438: OS9; NbExp=2; IntAct=EBI-15600828, EBI-725454;
CC O75460-1; Q9UBV2: SEL1L; NbExp=2; IntAct=EBI-15600828, EBI-358766;
CC O75460-1; Q86TM6: SYVN1; NbExp=3; IntAct=EBI-15600828, EBI-947849;
CC O75460-2; Q6DHV7-2: ADAL; NbExp=3; IntAct=EBI-25852368, EBI-18899653;
CC O75460-2; Q96MA6: AK8; NbExp=3; IntAct=EBI-25852368, EBI-8466265;
CC O75460-2; Q66PJ3-4: ARL6IP4; NbExp=3; IntAct=EBI-25852368, EBI-5280499;
CC O75460-2; Q9UBL3: ASH2L; NbExp=3; IntAct=EBI-25852368, EBI-540797;
CC O75460-2; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-25852368, EBI-9089489;
CC O75460-2; Q8TBE0: BAHD1; NbExp=3; IntAct=EBI-25852368, EBI-742750;
CC O75460-2; Q9BRT8: CBWD1; NbExp=3; IntAct=EBI-25852368, EBI-1054417;
CC O75460-2; Q9NNX6-10: CD209; NbExp=3; IntAct=EBI-25852368, EBI-12300031;
CC O75460-2; P38936: CDKN1A; NbExp=3; IntAct=EBI-25852368, EBI-375077;
CC O75460-2; Q96EY1-3: DNAJA3; NbExp=3; IntAct=EBI-25852368, EBI-11526226;
CC O75460-2; A0A024RCP2: DOM3Z; NbExp=3; IntAct=EBI-25852368, EBI-25847826;
CC O75460-2; Q92782-2: DPF1; NbExp=3; IntAct=EBI-25852368, EBI-23669343;
CC O75460-2; Q06547-2: GABPB1; NbExp=3; IntAct=EBI-25852368, EBI-618189;
CC O75460-2; Q06547-3: GABPB1; NbExp=3; IntAct=EBI-25852368, EBI-9088619;
CC O75460-2; P52655: GTF2A1; NbExp=3; IntAct=EBI-25852368, EBI-389518;
CC O75460-2; Q0VD86: INCA1; NbExp=3; IntAct=EBI-25852368, EBI-6509505;
CC O75460-2; Q92615: LARP4B; NbExp=3; IntAct=EBI-25852368, EBI-1052558;
CC O75460-2; Q6PHZ7: NR2C2; NbExp=3; IntAct=EBI-25852368, EBI-2802743;
CC O75460-2; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-25852368, EBI-25830200;
CC O75460-2; Q8N2H9-4: PELI3; NbExp=3; IntAct=EBI-25852368, EBI-25852006;
CC O75460-2; O15534: PER1; NbExp=3; IntAct=EBI-25852368, EBI-2557276;
CC O75460-2; Q58EX7-2: PLEKHG4; NbExp=3; IntAct=EBI-25852368, EBI-21503705;
CC O75460-2; Q5SXH7-1: PLEKHS1; NbExp=3; IntAct=EBI-25852368, EBI-26412802;
CC O75460-2; Q14181: POLA2; NbExp=3; IntAct=EBI-25852368, EBI-712752;
CC O75460-2; Q9UHI5: SLC7A8; NbExp=3; IntAct=EBI-25852368, EBI-13292283;
CC O75460-2; O14544: SOCS6; NbExp=3; IntAct=EBI-25852368, EBI-3929549;
CC O75460-2; Q496A3: SPATS1; NbExp=3; IntAct=EBI-25852368, EBI-3923692;
CC O75460-2; Q8IUR5-4: TMTC1; NbExp=3; IntAct=EBI-25852368, EBI-9089156;
CC O75460-2; P49459: UBE2A; NbExp=3; IntAct=EBI-25852368, EBI-2339348;
CC O75460-2; Q9NX94: WBP1L; NbExp=3; IntAct=EBI-25852368, EBI-10316321;
CC O75460-2; Q9BYN7-2: ZNF341; NbExp=3; IntAct=EBI-25852368, EBI-16435478;
CC O75460-2; Q3KNS6-3: ZNF829; NbExp=3; IntAct=EBI-25852368, EBI-18036029;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:9637683}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:9637683}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O75460-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O75460-2; Sequence=VSP_034582, VSP_034583;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. High levels observed in
CC pancreatic tissue. {ECO:0000269|PubMed:9637683}.
CC -!- PTM: Autophosphorylated following homodimerization. Autophosphorylation
CC promotes activation of the endoribonuclease domain.
CC {ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875,
CC ECO:0000269|PubMed:28128204, ECO:0000269|PubMed:9637683}.
CC -!- PTM: ADP-ribosylated by PARP16 upon ER stress, which increases both
CC kinase and endonuclease activities. {ECO:0000269|PubMed:23103912}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; AF059198; AAC25991.1; -; mRNA.
DR EMBL; AK292403; BAF85092.1; -; mRNA.
DR EMBL; DA254477; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AB209869; BAD93106.1; -; mRNA.
DR EMBL; AC005803; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC025362; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94214.1; -; Genomic_DNA.
DR EMBL; BC130405; AAI30406.1; -; mRNA.
DR EMBL; BC130407; AAI30408.1; -; mRNA.
DR EMBL; BI912495; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS45762.1; -. [O75460-1]
DR RefSeq; NP_001424.3; NM_001433.3. [O75460-1]
DR PDB; 2HZ6; X-ray; 3.10 A; A=24-390.
DR PDB; 3P23; X-ray; 2.70 A; A/B/C/D=547-977.
DR PDB; 4U6R; X-ray; 2.50 A; A=547-977.
DR PDB; 4YZ9; X-ray; 2.46 A; A/B/C=562-966.
DR PDB; 4YZC; X-ray; 2.49 A; A/B=562-966.
DR PDB; 4YZD; X-ray; 3.10 A; A/B/C=562-966.
DR PDB; 4Z7G; X-ray; 2.60 A; A/B=562-977.
DR PDB; 4Z7H; X-ray; 2.90 A; A/B=562-977.
DR PDB; 5HGI; X-ray; 2.58 A; A=547-977.
DR PDB; 6HV0; X-ray; 2.73 A; A=562-977.
DR PDB; 6HX1; X-ray; 2.14 A; A=562-964.
DR PDB; 6SHC; X-ray; 3.55 A; A=24-390.
DR PDB; 6URC; X-ray; 2.20 A; A/B=547-977.
DR PDB; 6W39; X-ray; 1.74 A; A/B=547-977.
DR PDB; 6W3A; X-ray; 2.61 A; A/B=547-977.
DR PDB; 6W3B; X-ray; 2.57 A; A=547-977.
DR PDB; 6W3C; X-ray; 2.30 A; A/B/C/D=547-977.
DR PDB; 6W3E; X-ray; 2.74 A; A/B=547-977.
DR PDB; 6W3K; X-ray; 2.08 A; A=547-977.
DR PDB; 6XDB; X-ray; 2.45 A; A=547-977.
DR PDB; 6XDD; X-ray; 2.40 A; A/B=547-977.
DR PDB; 6XDF; X-ray; 2.54 A; A/B=547-977.
DR PDB; 7BMK; X-ray; 1.85 A; A/B=547-977.
DR PDBsum; 2HZ6; -.
DR PDBsum; 3P23; -.
DR PDBsum; 4U6R; -.
DR PDBsum; 4YZ9; -.
DR PDBsum; 4YZC; -.
DR PDBsum; 4YZD; -.
DR PDBsum; 4Z7G; -.
DR PDBsum; 4Z7H; -.
DR PDBsum; 5HGI; -.
DR PDBsum; 6HV0; -.
DR PDBsum; 6HX1; -.
DR PDBsum; 6SHC; -.
DR PDBsum; 6URC; -.
DR PDBsum; 6W39; -.
DR PDBsum; 6W3A; -.
DR PDBsum; 6W3B; -.
DR PDBsum; 6W3C; -.
DR PDBsum; 6W3E; -.
DR PDBsum; 6W3K; -.
DR PDBsum; 6XDB; -.
DR PDBsum; 6XDD; -.
DR PDBsum; 6XDF; -.
DR PDBsum; 7BMK; -.
DR AlphaFoldDB; O75460; -.
DR SMR; O75460; -.
DR BioGRID; 108391; 60.
DR DIP; DIP-31711N; -.
DR IntAct; O75460; 56.
DR MINT; O75460; -.
DR STRING; 9606.ENSP00000401445; -.
DR BindingDB; O75460; -.
DR ChEMBL; CHEMBL1163101; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB07382; N~2~-1H-benzimidazol-5-yl-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine.
DR DrugCentral; O75460; -.
DR GuidetoPHARMACOLOGY; 2020; -.
DR TCDB; 8.A.104.1.9; the 5'-amp-activated protein kinase (ampk) family.
DR GlyGen; O75460; 1 site.
DR iPTMnet; O75460; -.
DR PhosphoSitePlus; O75460; -.
DR BioMuta; ERN1; -.
DR EPD; O75460; -.
DR jPOST; O75460; -.
DR MassIVE; O75460; -.
DR MaxQB; O75460; -.
DR PaxDb; O75460; -.
DR PeptideAtlas; O75460; -.
DR PRIDE; O75460; -.
DR ProteomicsDB; 50021; -. [O75460-1]
DR Antibodypedia; 4011; 717 antibodies from 44 providers.
DR DNASU; 2081; -.
DR Ensembl; ENST00000433197.4; ENSP00000401445.2; ENSG00000178607.17. [O75460-1]
DR Ensembl; ENST00000606895.2; ENSP00000475519.1; ENSG00000178607.17. [O75460-2]
DR GeneID; 2081; -.
DR KEGG; hsa:2081; -.
DR MANE-Select; ENST00000433197.4; ENSP00000401445.2; NM_001433.5; NP_001424.3.
DR UCSC; uc002jdz.3; human. [O75460-1]
DR CTD; 2081; -.
DR DisGeNET; 2081; -.
DR GeneCards; ERN1; -.
DR HGNC; HGNC:3449; ERN1.
DR HPA; ENSG00000178607; Tissue enhanced (adrenal gland, pancreas).
DR MIM; 604033; gene.
DR neXtProt; NX_O75460; -.
DR OpenTargets; ENSG00000178607; -.
DR PharmGKB; PA27861; -.
DR VEuPathDB; HostDB:ENSG00000178607; -.
DR eggNOG; KOG1027; Eukaryota.
DR GeneTree; ENSGT00940000159761; -.
DR HOGENOM; CLU_004875_1_1_1; -.
DR InParanoid; O75460; -.
DR OMA; HYLPDPR; -.
DR OrthoDB; 1019877at2759; -.
DR PhylomeDB; O75460; -.
DR TreeFam; TF313986; -.
DR PathwayCommons; O75460; -.
DR Reactome; R-HSA-381070; IRE1alpha activates chaperones.
DR SignaLink; O75460; -.
DR SIGNOR; O75460; -.
DR BioGRID-ORCS; 2081; 13 hits in 1109 CRISPR screens.
DR ChiTaRS; ERN1; human.
DR EvolutionaryTrace; O75460; -.
DR GeneWiki; ERN1; -.
DR GenomeRNAi; 2081; -.
DR Pharos; O75460; Tchem.
DR PRO; PR:O75460; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; O75460; protein.
DR Bgee; ENSG00000178607; Expressed in parotid gland and 157 other tissues.
DR Genevisible; O75460; HS.
DR GO; GO:1990597; C:AIP1-IRE1 complex; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:1990332; C:Ire1 complex; NAS:ParkinsonsUK-UCL.
DR GO; GO:1990630; C:IRE1-RACK1-PP2A complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990604; C:IRE1-TRAF2-ASK1 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005637; C:nuclear inner membrane; IEA:Ensembl.
DR GO; GO:0043531; F:ADP binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004521; F:endoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0051879; F:Hsp90 protein binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0005161; F:platelet-derived growth factor receptor binding; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; IBA:GO_Central.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0034620; P:cellular response to unfolded protein; IDA:ParkinsonsUK-UCL.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0001935; P:endothelial cell proliferation; IDA:UniProtKB.
DR GO; GO:1901142; P:insulin metabolic process; IDA:ParkinsonsUK-UCL.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0036498; P:IRE1-mediated unfolded protein response; IDA:UniProtKB.
DR GO; GO:0006402; P:mRNA catabolic process; TAS:ParkinsonsUK-UCL.
DR GO; GO:0006379; P:mRNA cleavage; ISS:UniProtKB.
DR GO; GO:0098787; P:mRNA cleavage involved in mRNA processing; IDA:ParkinsonsUK-UCL.
DR GO; GO:0070054; P:mRNA splicing, via endonucleolytic cleavage and ligation; IDA:UniProtKB.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990579; P:peptidyl-serine trans-autophosphorylation; IMP:ParkinsonsUK-UCL.
DR GO; GO:1900103; P:positive regulation of endoplasmic reticulum unfolded protein response; IMP:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0033120; P:positive regulation of RNA splicing; IDA:UniProtKB.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL.
DR Gene3D; 1.20.1440.180; -; 1.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR045133; IRE1/2-like.
DR InterPro; IPR010513; KEN_dom.
DR InterPro; IPR038357; KEN_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR018391; PQQ_beta_propeller_repeat.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR011047; Quinoprotein_ADH-like_supfam.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR PANTHER; PTHR13954; PTHR13954; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF06479; Ribonuc_2-5A; 1.
DR SMART; SM00564; PQQ; 5.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF50998; SSF50998; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51392; KEN; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ADP-ribosylation; Alternative splicing; Apoptosis;
KW ATP-binding; Disulfide bond; Endoplasmic reticulum; Glycoprotein;
KW Hydrolase; Kinase; Magnesium; Membrane; Metal-binding;
KW Multifunctional enzyme; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Signal; Transcription;
KW Transcription regulation; Transferase; Transmembrane; Transmembrane helix;
KW Unfolded protein response.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..977
FT /note="Serine/threonine-protein kinase/endoribonuclease
FT IRE1"
FT /id="PRO_0000024327"
FT TOPO_DOM 19..443
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 444..464
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 465..977
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 571..832
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 835..963
FT /note="KEN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00725"
FT REGION 410..434
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 491..559
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 906..907
FT /note="Interacts with hydroxy-aryl-aldehyde inhibitors"
FT /evidence="ECO:0000250|UniProtKB:Q9EQY0"
FT COMPBIAS 511..551
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 688
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P32361,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 577..585
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P32361,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 599
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683,
FT ECO:0007744|PDB:3P23"
FT BINDING 643..645
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:21317875,
FT ECO:0007744|PDB:3P23"
FT BINDING 690..693
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:21317875,
FT ECO:0007744|PDB:3P23"
FT BINDING 711
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:21317875,
FT ECO:0007744|PDB:3P23"
FT SITE 892
FT /note="Interacts with hydroxy-aryl-aldehyde inhibitors"
FT /evidence="ECO:0000250|UniProtKB:Q9EQY0"
FT MOD_RES 973
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT CARBOHYD 176
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 19..70
FT /note="IFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDPVLQVPTHVEE
FT -> VSDRGAWGGGQLATAGSGPGQRRGAGAGVRAGSATAAARCPVSPAVGGSGRA (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_034582"
FT VAR_SEQ 71..977
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_034583"
FT VARIANT 244
FT /note="N -> S (in a renal clear cell carcinoma sample;
FT somatic mutation; dbSNP:rs1397145500)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040488"
FT VARIANT 418
FT /note="V -> M (in dbSNP:rs55869215)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040489"
FT VARIANT 474
FT /note="L -> R (in a lung adenocarcinoma sample; somatic
FT mutation; dbSNP:rs186305118)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040490"
FT VARIANT 635
FT /note="R -> W (in a gastric adenocarcinoma sample; somatic
FT mutation; dbSNP:rs146710304)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040491"
FT VARIANT 700
FT /note="N -> S (in dbSNP:rs918253870)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040492"
FT VARIANT 769
FT /note="S -> F (in a glioblastoma multiforme sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040493"
FT VARIANT 830
FT /note="P -> L (in an ovarian serous carcinoma sample;
FT somatic mutation; dbSNP:rs1279653488)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040494"
FT MUTAGEN 105
FT /note="Q->E: Impaired ability to homodimerize."
FT /evidence="ECO:0000269|PubMed:16973740"
FT MUTAGEN 109
FT /note="C->S: No effect on dimerization. No effect on
FT interaction with P4HB; when associated with S-148 and S-
FT 332."
FT /evidence="ECO:0000269|PubMed:12637535,
FT ECO:0000269|PubMed:32149426"
FT MUTAGEN 123
FT /note="D->P: Abolishes ability to homodimerize."
FT /evidence="ECO:0000269|PubMed:16973740"
FT MUTAGEN 125
FT /note="W->A: Abolishes ability to homodimerize."
FT /evidence="ECO:0000269|PubMed:16973740"
FT MUTAGEN 148
FT /note="C->S: No effect on dimerization. Weakens dimer; when
FT associated with S-332. Abolishes interaction with PDIA6.
FT Prolonged splicing of XBP1, probably due to prolonged
FT activation of PDIA6. Inhibits formation of oxidized
FT multimeric forms of ERN1 in response to ER stress. No
FT effect on interaction with P4HB; when associated with S-109
FT and S-332."
FT /evidence="ECO:0000269|PubMed:12637535,
FT ECO:0000269|PubMed:24508390, ECO:0000269|PubMed:32149426"
FT MUTAGEN 332
FT /note="C->S: No effect on dimerization. Weakens dimer; when
FT associated with S-148. No effect on interaction with P4HB;
FT when associated with S-109 and S-148."
FT /evidence="ECO:0000269|PubMed:12637535,
FT ECO:0000269|PubMed:32149426"
FT MUTAGEN 599
FT /note="K->A: Loss of autophosphorylation and of
FT endoribonuclease activity. Inhibition of growth arrest."
FT /evidence="ECO:0000269|PubMed:11175748,
FT ECO:0000269|PubMed:9637683"
FT CONFLICT 190..191
FT /note="DV -> EG (in Ref. 1; AAC25991)"
FT /evidence="ECO:0000305"
FT CONFLICT 768
FT /note="I -> V (in Ref. 1; AAC25991)"
FT /evidence="ECO:0000305"
FT CONFLICT 816
FT /note="D -> G (in Ref. 2; BAF85092)"
FT /evidence="ECO:0000305"
FT CONFLICT 824..825
FT /note="KH -> ND (in Ref. 1; AAC25991)"
FT /evidence="ECO:0000305"
FT CONFLICT 880
FT /note="V -> D (in Ref. 1; AAC25991)"
FT /evidence="ECO:0000305"
FT CONFLICT 904
FT /note="M -> T (in Ref. 2; BAF85092)"
FT /evidence="ECO:0000305"
FT CONFLICT 924
FT /note="S -> T (in Ref. 1; AAC25991)"
FT /evidence="ECO:0000305"
FT STRAND 32..37
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 40..46
FT /evidence="ECO:0007829|PDB:2HZ6"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 52..57
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 73..75
FT /evidence="ECO:0007829|PDB:2HZ6"
FT TURN 77..79
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 82..84
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 93..95
FT /evidence="ECO:0007829|PDB:2HZ6"
FT HELIX 100..104
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 120..128
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 154..164
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 168..172
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 176..182
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 197..201
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 205..209
FT /evidence="ECO:0007829|PDB:2HZ6"
FT TURN 211..213
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 216..221
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 226..231
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 238..240
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 243..246
FT /evidence="ECO:0007829|PDB:2HZ6"
FT HELIX 247..264
FT /evidence="ECO:0007829|PDB:2HZ6"
FT HELIX 273..279
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 280..284
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 286..288
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 297..300
FT /evidence="ECO:0007829|PDB:2HZ6"
FT TURN 359..361
FT /evidence="ECO:0007829|PDB:2HZ6"
FT STRAND 564..566
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 569..578
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 581..583
FT /evidence="ECO:0007829|PDB:6HX1"
FT STRAND 585..591
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 594..601
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 603..605
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 606..619
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 628..633
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 638..643
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 645..648
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 649..654
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 655..657
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 658..661
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 665..681
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 691..693
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 694..697
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 701..703
FT /evidence="ECO:0007829|PDB:6W3E"
FT STRAND 707..709
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 711..716
FT /evidence="ECO:0007829|PDB:6HX1"
FT STRAND 718..721
FT /evidence="ECO:0007829|PDB:6HV0"
FT STRAND 723..727
FT /evidence="ECO:0007829|PDB:6HX1"
FT STRAND 729..731
FT /evidence="ECO:0007829|PDB:6HV0"
FT TURN 732..736
FT /evidence="ECO:0007829|PDB:6HV0"
FT HELIX 740..743
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 744..746
FT /evidence="ECO:0007829|PDB:6XDF"
FT HELIX 754..768
FT /evidence="ECO:0007829|PDB:6W39"
FT TURN 778..780
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 781..787
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 793..795
FT /evidence="ECO:0007829|PDB:4YZC"
FT HELIX 800..812
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 817..819
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 823..827
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 830..832
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 835..848
FT /evidence="ECO:0007829|PDB:6W39"
FT TURN 849..851
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 854..856
FT /evidence="ECO:0007829|PDB:4YZ9"
FT HELIX 857..863
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 866..869
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 874..876
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 880..884
FT /evidence="ECO:0007829|PDB:6W39"
FT TURN 887..890
FT /evidence="ECO:0007829|PDB:6W3K"
FT HELIX 897..909
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 911..913
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 916..922
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 927..936
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 940..947
FT /evidence="ECO:0007829|PDB:6W39"
FT HELIX 948..951
FT /evidence="ECO:0007829|PDB:6W39"
FT STRAND 952..954
FT /evidence="ECO:0007829|PDB:3P23"
FT HELIX 955..957
FT /evidence="ECO:0007829|PDB:6W39"
FT TURN 958..960
FT /evidence="ECO:0007829|PDB:6W39"
SQ SEQUENCE 977 AA; 109735 MW; A2DF808CCE015536 CRC64;
MPARRLLLLL TLLLPGLGIF GSTSTVTLPE TLLFVSTLDG SLHAVSKRTG SIKWTLKEDP
VLQVPTHVEE PAFLPDPNDG SLYTLGSKNN EGLTKLPFTI PELVQASPCR SSDGILYMGK
KQDIWYVIDL LTGEKQQTLS SAFADSLCPS TSLLYLGRTE YTITMYDTKT RELRWNATYF
DYAASLPEDD VDYKMSHFVS NGDGLVVTVD SESGDVLWIQ NYASPVVAFY VWQREGLRKV
MHINVAVETL RYLTFMSGEV GRITKWKYPF PKETEAKSKL TPTLYVGKYS TSLYASPSMV
HEGVAVVPRG STLPLLEGPQ TDGVTIGDKG ECVITPSTDV KFDPGLKSKN KLNYLRNYWL
LIGHHETPLS ASTKMLERFP NNLPKHRENV IPADSEKKSF EEVINLVDQT SENAPTTVSR
DVEEKPAHAP ARPEAPVDSM LKDMATIILS TFLLIGWVAF IITYPLSMHQ QQQLQHQQFQ
KELEKIQLLQ QQQQQLPFHP PGDTAQDGEL LDTSGPYSES SGTSSPSTSP RASNHSLCSG
SSASKAGSSP SLEQDDGDEE TSVVIVGKIS FCPKDVLGHG AEGTIVYRGM FDNRDVAVKR
ILPECFSFAD REVQLLRESD EHPNVIRYFC TEKDRQFQYI AIELCAATLQ EYVEQKDFAH
LGLEPITLLQ QTTSGLAHLH SLNIVHRDLK PHNILISMPN AHGKIKAMIS DFGLCKKLAV
GRHSFSRRSG VPGTEGWIAP EMLSEDCKEN PTYTVDIFSA GCVFYYVISE GSHPFGKSLQ
RQANILLGAC SLDCLHPEKH EDVIARELIE KMIAMDPQKR PSAKHVLKHP FFWSLEKQLQ
FFQDVSDRIE KESLDGPIVK QLERGGRAVV KMDWRENITV PLQTDLRKFR TYKGGSVRDL
LRAMRNKKHH YRELPAEVRE TLGSLPDDFV CYFTSRFPHL LAHTYRAMEL CSHERLFQPY
YFHEPPEPQP PVTPDAL
