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 13-FEB-2019, entry version 189. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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, RP AUTOPHOSPHORYLATION, 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 RT nucleus requires a novel bifunctional protein kinase/endoribonuclease RT (Ire1p) in 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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., RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., RA 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 RT the 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., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA 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 RP SEQUENCE [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 RT project: 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 RT stress 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., RA Tohyama M.; RT "Activation of caspase-12, an endoplastic reticulum (ER) resident RT caspase, through tumor necrosis factor receptor-associated factor 2- RT dependent 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 RT IRE1 under ER stress."; RL Nat. Cell Biol. 3:158-164(2001). RN [10] {ECO:0000305} RP FUNCTION, HOMODIMERIZATION, ACTIVITY REGULATION, INTERACTION WITH RP HSPA5, 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 RP BY 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., RA Buerckstuemmer T., 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 RT the 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 RT the unfolded protein response."; RL Cell 171:1625-1637(2017). RN [15] {ECO:0000244|PDB:2HZ6} RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 24-390, SUBUNIT, AND RP MUTAGENESIS 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., RA Kaufman R.J.; RT "The crystal structure of human IRE1 luminal domain reveals a RT conserved dimerization interface required for activation of the RT unfolded protein response."; RL Proc. Natl. Acad. Sci. U.S.A. 103:14343-14348(2006). RN [16] {ECO:0000244|PDB:3P23} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 547-977 IN COMPLEX WITH ADP, RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP AUTOPHOSPHORYLATION, AND COFACTOR. RX PubMed=21317875; DOI=10.1038/emboj.2011.18; RA Ali M.M., Bagratuni T., Davenport E.L., Nowak P.R., RA Silva-Santisteban M.C., Hardcastle A., McAndrews C., Rowlands M.G., RA Morgan G.J., Aherne W., Collins I., Davies F.E., Pearl L.H.; RT "Structure of the Ire1 autophosphorylation complex and implications RT for the unfolded protein response."; RL EMBO J. 30:894-905(2011). RN [17] 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., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [18] 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 RT unconventional secretion pathway."; RL Cell 146:746-760(2011). RN [19] 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 RT signaling via disulfide-dependent association."; RL Mol. Cell 53:562-576(2014). RN [20] 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 RT of CFTR."; RL Sci. Rep. 7:39887-39887(2017). CC -!- FUNCTION: Serine/threonine-protein kinase and endoribonuclease CC that acts as a key sensor for the endoplasmic reticulum unfolded CC protein response (UPR) (PubMed:11779464, PubMed:11175748, CC PubMed:12637535, PubMed:9637683, PubMed:21317875). In unstressed CC cells, the endoplasmic reticulum luminal domain is maintained in CC its inactive monomeric state by binding to the endoplasmic CC reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of CC misfolded protein in the endoplasmic reticulum causes release of CC HSPA5/BiP, allowing the luminal domain to homodimerize, promoting CC autophosphorylation of the kinase domain and subsequent activation CC of the endoribonuclease activity (PubMed:21317875). The CC endoribonuclease activity is specific for XBP1 mRNA and excises 26 CC nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, CC PubMed:21317875). The resulting spliced transcript of XBP1 encodes CC a transcriptional activator protein that up-regulates expression CC 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 CC of CFTR to cell membrane by modulating the expression and CC localization of 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:9637683, 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, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21317875, CC 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, CC 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- CC aryl-aldehydes (HAA) (By similarity). CC {ECO:0000250|UniProtKB:Q9EQY0, ECO:0000269|PubMed:12637535, CC 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 CC and 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 CC the 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 CC HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded CC protein response (UPR) that prevents homodimerization of ERN1/IRE1 CC and subsequent activation of the protein (PubMed:12637535, CC PubMed:29198525). Interacts with PDIA6, a negative regulator of CC the UPR; the interaction is direct and disrupts homodimerization CC (PubMed:24508390). Interacts with DAB2IP (via PH domain); the CC interaction occurs in a endoplasmic reticulum stress-induced CC dependent manner and is required for subsequent recruitment of CC TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 CC (PubMed:11278723). {ECO:0000250|UniProtKB:Q9EQY0, CC ECO:0000269|PubMed:11278723, ECO:0000269|PubMed:12637535, CC ECO:0000269|PubMed:16973740, ECO:0000269|PubMed:24508390, CC ECO:0000269|PubMed:29198525}. CC -!- INTERACTION: CC Self; NbExp=2; IntAct=EBI-371750, EBI-371750; CC O08734:Bak1 (xeno); NbExp=2; IntAct=EBI-371750, EBI-822441; CC Q07812:BAX; NbExp=2; IntAct=EBI-371750, EBI-516580; CC Q07813:Bax (xeno); NbExp=2; IntAct=EBI-371750, EBI-700711; CC P0DMV8:HSPA1A; NbExp=5; IntAct=EBI-15600828, EBI-11820565; CC P11021:HSPA5; NbExp=4; IntAct=EBI-15600828, EBI-354921; CC P20029:Hspa5 (xeno); NbExp=2; IntAct=EBI-371750, EBI-772325; CC Q13438:OS9; NbExp=2; IntAct=EBI-15600828, EBI-725454; CC Q9UBV2:SEL1L; NbExp=2; IntAct=EBI-15600828, EBI-358766; CC Q86TM6:SYVN1; NbExp=3; IntAct=EBI-15600828, EBI-947849; CC Q9H2K8:TAOK3; NbExp=3; IntAct=EBI-371750, EBI-1384100; CC Q12933:TRAF2; NbExp=3; IntAct=EBI-371750, EBI-355744; CC Q969M3:YIPF5; NbExp=3; IntAct=EBI-371750, EBI-2124787; 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 CC in pancreatic tissue. {ECO:0000269|PubMed:9637683}. CC -!- PTM: Autophosphorylated following homodimerization. CC Autophosphorylation promotes activation of the endoribonuclease CC domain. {ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875, CC ECO:0000269|PubMed:9637683}. CC -!- PTM: ADP-ribosylated by PARP16 upon ER stress, which increases CC both kinase and endonuclease activities. CC {ECO:0000269|PubMed:23103912}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr CC protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- 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 UniGene; Hs.133982; -. DR UniGene; Hs.700027; -. DR UniGene; Hs.744953; -. 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 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 ProteinModelPortal; O75460; -. DR SMR; O75460; -. DR BioGrid; 108391; 33. DR DIP; DIP-31711N; -. DR IntAct; O75460; 22. DR MINT; O75460; -. DR STRING; 9606.ENSP00000401445; -. DR BindingDB; O75460; -. DR ChEMBL; CHEMBL1163101; -. DR GuidetoPHARMACOLOGY; 2020; -. DR iPTMnet; O75460; -. DR PhosphoSitePlus; O75460; -. DR BioMuta; ERN1; -. DR EPD; O75460; -. DR jPOST; O75460; -. DR MaxQB; O75460; -. DR PaxDb; O75460; -. DR PeptideAtlas; O75460; -. DR PRIDE; O75460; -. DR ProteomicsDB; 50021; -. DR ProteomicsDB; 50022; -. [O75460-2] DR DNASU; 2081; -. DR Ensembl; ENST00000433197; ENSP00000401445; ENSG00000178607. [O75460-1] DR Ensembl; ENST00000606895; ENSP00000475519; ENSG00000178607. [O75460-2] DR GeneID; 2081; -. DR KEGG; hsa:2081; -. DR UCSC; uc002jdz.3; human. [O75460-1] DR CTD; 2081; -. DR DisGeNET; 2081; -. DR EuPathDB; HostDB:ENSG00000178607.15; -. DR GeneCards; ERN1; -. DR H-InvDB; HIX0014084; -. DR HGNC; HGNC:3449; ERN1. DR HPA; CAB009495; -. DR HPA; HPA027730; -. DR MIM; 604033; gene. DR neXtProt; NX_O75460; -. DR OpenTargets; ENSG00000178607; -. DR PharmGKB; PA27861; -. DR eggNOG; KOG1027; Eukaryota. DR eggNOG; COG0515; LUCA. DR GeneTree; ENSGT00940000159761; -. DR HOGENOM; HOG000012929; -. DR HOVERGEN; HBG051506; -. DR InParanoid; O75460; -. DR KO; K08852; -. DR OMA; RYFTSRF; -. DR OrthoDB; 1019877at2759; -. DR PhylomeDB; O75460; -. DR TreeFam; TF313986; -. DR Reactome; R-HSA-381070; IRE1alpha activates chaperones. DR SignaLink; O75460; -. DR SIGNOR; O75460; -. DR ChiTaRS; ERN1; human. DR EvolutionaryTrace; O75460; -. DR GeneWiki; ERN1; -. DR GenomeRNAi; 2081; -. DR PRO; PR:O75460; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; ENSG00000178607; Expressed in 180 organ(s), highest expression level in adrenal gland. 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; IBA:GO_Central. 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:0004672; F:protein kinase activity; IBA:GO_Central. 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:0007257; P:activation of JUN kinase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0007050; P:cell cycle arrest; ISS:UniProtKB. DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:ParkinsonsUK-UCL. 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:0030968; P:endoplasmic reticulum unfolded protein response; IBA:GO_Central. 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; IBA:GO_Central. 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:0033120; P:positive regulation of RNA splicing; IDA:UniProtKB. DR GO; GO:1904707; P:positive regulation of vascular 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; 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; IPR018997; PUB_domain. DR InterPro; IPR011047; Quinoprotein_ADH-like_supfam. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF06479; Ribonuc_2-5A; 1. DR SMART; SM00564; PQQ; 5. DR SMART; SM00580; PUG; 1. 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; Complete proteome; Disulfide bond; Endoplasmic reticulum; KW Glycoprotein; Hydrolase; Kinase; Magnesium; Membrane; Metal-binding; KW Multifunctional enzyme; Nucleotide-binding; Phosphoprotein; KW Polymorphism; Reference proteome; Serine/threonine-protein kinase; KW Signal; Transcription; Transcription regulation; Transferase; KW Transmembrane; Transmembrane helix; Unfolded protein response. FT SIGNAL 1 18 {ECO:0000255}. FT CHAIN 19 977 Serine/threonine-protein FT kinase/endoribonuclease IRE1. FT /FTId=PRO_0000024327. FT TOPO_DOM 19 443 Lumenal. {ECO:0000255}. FT TRANSMEM 444 464 Helical. {ECO:0000255}. FT TOPO_DOM 465 977 Cytoplasmic. {ECO:0000255}. FT DOMAIN 571 832 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT DOMAIN 835 963 KEN. {ECO:0000255|PROSITE- FT ProRule:PRU00725}. FT NP_BIND 577 585 ATP. {ECO:0000250|UniProtKB:P32361, FT ECO:0000255|PROSITE-ProRule:PRU00159}. FT NP_BIND 643 645 ATP. {ECO:0000244|PDB:3P23, FT ECO:0000269|PubMed:21317875}. FT NP_BIND 690 693 ATP. {ECO:0000244|PDB:3P23, FT ECO:0000269|PubMed:21317875}. FT REGION 906 907 Hydroxy-aryl-aldehyde inhibitor binding. FT {ECO:0000250|UniProtKB:Q9EQY0}. FT ACT_SITE 688 688 Proton acceptor. FT {ECO:0000250|UniProtKB:P32361, FT ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027}. FT BINDING 599 599 ATP. {ECO:0000244|PDB:3P23, FT ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:21317875, FT ECO:0000269|PubMed:9637683}. FT BINDING 711 711 ATP. {ECO:0000244|PDB:3P23, FT ECO:0000269|PubMed:21317875}. FT BINDING 892 892 Hydroxy-aryl-aldehyde inhibitor. FT {ECO:0000250|UniProtKB:Q9EQY0}. FT MOD_RES 973 973 Phosphothreonine. FT {ECO:0000244|PubMed:19369195}. FT CARBOHYD 176 176 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT VAR_SEQ 19 70 IFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKED FT PVLQVPTHVEE -> VSDRGAWGGGQLATAGSGPGQRRGAG FT AGVRAGSATAAARCPVSPAVGGSGRA (in isoform FT 2). {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334}. FT /FTId=VSP_034582. FT VAR_SEQ 71 977 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334}. FT /FTId=VSP_034583. FT VARIANT 244 244 N -> S (in a renal clear cell carcinoma FT sample; somatic mutation; FT dbSNP:rs1397145500). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040488. FT VARIANT 418 418 V -> M (in dbSNP:rs55869215). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040489. FT VARIANT 474 474 L -> R (in a lung adenocarcinoma sample; FT somatic mutation; dbSNP:rs186305118). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040490. FT VARIANT 635 635 R -> W (in a gastric adenocarcinoma FT sample; somatic mutation; FT dbSNP:rs146710304). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040491. FT VARIANT 700 700 N -> S (in dbSNP:rs918253870). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040492. FT VARIANT 769 769 S -> F (in a glioblastoma multiforme FT sample; somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040493. FT VARIANT 830 830 P -> L (in an ovarian serous carcinoma FT sample; somatic mutation; FT dbSNP:rs1279653488). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040494. FT MUTAGEN 105 105 Q->E: Impaired ability to homodimerize. FT {ECO:0000269|PubMed:16973740}. FT MUTAGEN 109 109 C->S: No effect on dimerization. FT {ECO:0000269|PubMed:12637535}. FT MUTAGEN 123 123 D->P: Abolishes ability to homodimerize. FT {ECO:0000269|PubMed:16973740}. FT MUTAGEN 125 125 W->A: Abolishes ability to homodimerize. FT {ECO:0000269|PubMed:16973740}. FT MUTAGEN 148 148 C->S: No effect on dimerization. Weakens FT dimer; when associated with S-332. FT Abolishes interaction with PDIA6. FT Prolonged splicing of XBP1, probably due FT to prolonged activation of PDIA6. FT Inhibits formation of oxidized multimeric FT forms of ERN1 in response to ER stress. FT {ECO:0000269|PubMed:12637535, FT ECO:0000269|PubMed:24508390}. FT MUTAGEN 332 332 C->S: No effect on dimerization. Weakens FT dimer; when associated with S-148. FT {ECO:0000269|PubMed:12637535}. FT MUTAGEN 599 599 K->A: Loss of autophosphorylation and of FT endoribonuclease activity. Inhibition of FT growth arrest. FT {ECO:0000269|PubMed:11175748, FT ECO:0000269|PubMed:9637683}. FT CONFLICT 190 191 DV -> EG (in Ref. 1; AAC25991). FT {ECO:0000305}. FT CONFLICT 768 768 I -> V (in Ref. 1; AAC25991). FT {ECO:0000305}. FT CONFLICT 816 816 D -> G (in Ref. 2; BAF85092). FT {ECO:0000305}. FT CONFLICT 824 825 KH -> ND (in Ref. 1; AAC25991). FT {ECO:0000305}. FT CONFLICT 880 880 V -> D (in Ref. 1; AAC25991). FT {ECO:0000305}. FT CONFLICT 904 904 M -> T (in Ref. 2; BAF85092). FT {ECO:0000305}. FT CONFLICT 924 924 S -> T (in Ref. 1; AAC25991). FT {ECO:0000305}. FT STRAND 32 37 {ECO:0000244|PDB:2HZ6}. FT STRAND 40 46 {ECO:0000244|PDB:2HZ6}. FT TURN 47 49 {ECO:0000244|PDB:2HZ6}. FT STRAND 52 57 {ECO:0000244|PDB:2HZ6}. FT STRAND 73 75 {ECO:0000244|PDB:2HZ6}. FT TURN 77 79 {ECO:0000244|PDB:2HZ6}. FT STRAND 82 84 {ECO:0000244|PDB:2HZ6}. FT STRAND 93 95 {ECO:0000244|PDB:2HZ6}. FT HELIX 100 104 {ECO:0000244|PDB:2HZ6}. FT STRAND 120 128 {ECO:0000244|PDB:2HZ6}. FT STRAND 154 164 {ECO:0000244|PDB:2HZ6}. FT STRAND 168 172 {ECO:0000244|PDB:2HZ6}. FT STRAND 176 182 {ECO:0000244|PDB:2HZ6}. FT STRAND 197 201 {ECO:0000244|PDB:2HZ6}. FT STRAND 205 209 {ECO:0000244|PDB:2HZ6}. FT TURN 211 213 {ECO:0000244|PDB:2HZ6}. FT STRAND 216 221 {ECO:0000244|PDB:2HZ6}. FT STRAND 226 231 {ECO:0000244|PDB:2HZ6}. FT STRAND 238 240 {ECO:0000244|PDB:2HZ6}. FT STRAND 243 246 {ECO:0000244|PDB:2HZ6}. FT HELIX 247 264 {ECO:0000244|PDB:2HZ6}. FT HELIX 273 279 {ECO:0000244|PDB:2HZ6}. FT STRAND 280 284 {ECO:0000244|PDB:2HZ6}. FT STRAND 286 288 {ECO:0000244|PDB:2HZ6}. FT STRAND 297 300 {ECO:0000244|PDB:2HZ6}. FT TURN 359 361 {ECO:0000244|PDB:2HZ6}. FT STRAND 564 566 {ECO:0000244|PDB:4YZC}. FT STRAND 567 580 {ECO:0000244|PDB:4YZ9}. FT TURN 581 583 {ECO:0000244|PDB:4YZ9}. FT STRAND 584 591 {ECO:0000244|PDB:4YZ9}. FT STRAND 594 601 {ECO:0000244|PDB:4YZ9}. FT HELIX 603 605 {ECO:0000244|PDB:4YZ9}. FT HELIX 606 617 {ECO:0000244|PDB:4YZ9}. FT STRAND 628 633 {ECO:0000244|PDB:4YZ9}. FT STRAND 638 642 {ECO:0000244|PDB:4YZ9}. FT STRAND 645 648 {ECO:0000244|PDB:4YZ9}. FT HELIX 649 655 {ECO:0000244|PDB:4YZ9}. FT HELIX 657 661 {ECO:0000244|PDB:4YZ9}. FT HELIX 665 681 {ECO:0000244|PDB:4YZ9}. FT TURN 691 693 {ECO:0000244|PDB:4YZ9}. FT STRAND 694 697 {ECO:0000244|PDB:4YZ9}. FT TURN 701 703 {ECO:0000244|PDB:4YZD}. FT STRAND 707 709 {ECO:0000244|PDB:4YZ9}. FT HELIX 712 714 {ECO:0000244|PDB:4YZC}. FT HELIX 740 743 {ECO:0000244|PDB:4YZC}. FT HELIX 754 768 {ECO:0000244|PDB:4YZ9}. FT HELIX 778 780 {ECO:0000244|PDB:4YZ9}. FT HELIX 781 787 {ECO:0000244|PDB:4YZ9}. FT STRAND 793 795 {ECO:0000244|PDB:4YZC}. FT HELIX 800 812 {ECO:0000244|PDB:4YZ9}. FT HELIX 817 819 {ECO:0000244|PDB:4YZ9}. FT HELIX 823 827 {ECO:0000244|PDB:4YZ9}. FT HELIX 830 832 {ECO:0000244|PDB:4YZ9}. FT HELIX 835 849 {ECO:0000244|PDB:4YZ9}. FT STRAND 854 856 {ECO:0000244|PDB:4YZ9}. FT HELIX 857 865 {ECO:0000244|PDB:4YZ9}. FT HELIX 867 870 {ECO:0000244|PDB:4YZ9}. FT STRAND 874 878 {ECO:0000244|PDB:4YZ9}. FT HELIX 880 887 {ECO:0000244|PDB:4YZ9}. FT STRAND 888 890 {ECO:0000244|PDB:4YZ9}. FT HELIX 897 909 {ECO:0000244|PDB:4YZ9}. FT HELIX 911 913 {ECO:0000244|PDB:4YZ9}. FT HELIX 916 922 {ECO:0000244|PDB:4YZ9}. FT HELIX 927 936 {ECO:0000244|PDB:4YZ9}. FT HELIX 940 947 {ECO:0000244|PDB:4YZ9}. FT HELIX 948 951 {ECO:0000244|PDB:4YZ9}. FT STRAND 952 954 {ECO:0000244|PDB:3P23}. FT HELIX 955 957 {ECO:0000244|PDB:4YZ9}. FT TURN 958 960 {ECO:0000244|PDB:4YZ9}. 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 //