Full text data of PDIA6
PDIA6
(ERP5, P5, TXNDC7)
[Confidence: low (only semi-automatic identification from reviews)]
Protein disulfide-isomerase A6; 5.3.4.1 (Endoplasmic reticulum protein 5; ER protein 5; ERp5; Protein disulfide isomerase P5; Thioredoxin domain-containing protein 7; Flags: Precursor)
Protein disulfide-isomerase A6; 5.3.4.1 (Endoplasmic reticulum protein 5; ER protein 5; ERp5; Protein disulfide isomerase P5; Thioredoxin domain-containing protein 7; Flags: Precursor)
UniProt
Q15084
ID PDIA6_HUMAN Reviewed; 440 AA.
AC Q15084; Q53RC7; Q6ZSH5; Q99778;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Protein disulfide-isomerase A6;
DE EC=5.3.4.1;
DE AltName: Full=Endoplasmic reticulum protein 5;
DE Short=ER protein 5;
DE Short=ERp5;
DE AltName: Full=Protein disulfide isomerase P5;
DE AltName: Full=Thioredoxin domain-containing protein 7;
DE Flags: Precursor;
GN Name=PDIA6; Synonyms=ERP5, P5, TXNDC7;
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]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=7590364; DOI=10.1016/0378-1119(95)00474-K;
RA Hayano T., Kikuchi M.;
RT "Cloning and sequencing of the cDNA encoding human P5.";
RL Gene 164:377-378(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ARG-214.
RC TISSUE=Thalamus;
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 GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-440 (ISOFORM 1), AND
RP VARIANT ARG-214.
RC TISSUE=Brain;
RX PubMed=9110174;
RA Yu W., Andersson B., Worley K.C., Muzny D.M., Ding Y., Liu W.,
RA Ricafrente J.Y., Wentland M.A., Lennon G., Gibbs R.A.;
RT "Large-scale concatenation cDNA sequencing.";
RL Genome Res. 7:353-358(1997).
RN [7]
RP PROTEIN SEQUENCE [LARGE SCALE ANALYSIS] OF 20-38.
RC TISSUE=Leukemic T-cell;
RX PubMed=19892738; DOI=10.1073/pnas.0908958106;
RA Xu G., Shin S.B., Jaffrey S.R.;
RT "Global profiling of protease cleavage sites by chemoselective
RT labeling of protein N-termini.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:19310-19315(2009).
RN [8]
RP PROTEIN SEQUENCE OF 20-34, FUNCTION, ENZYME ACTIVITY, INTERACTION WITH
RP ITGB3, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15466936; DOI=10.1182/blood-2004-02-0608;
RA Jordan P.A., Stevens J.M., Hubbard G.P., Barrett N.E., Sage T.,
RA Authi K.S., Gibbins J.M.;
RT "A role for the thiol isomerase protein ERP5 in platelet function.";
RL Blood 105:1500-1507(2005).
RN [9]
RP PROTEIN SEQUENCE OF 103-138; 195-212; 217-231; 242-289; 314-328 AND
RP 374-386.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [10]
RP FUNCTION, ENZYME ACTIVITY, AND MUTAGENESIS OF CYS-55; CYS-58; CYS-190
RP AND CYS-193.
RX PubMed=12204115;
RA Kikuchi M., Doi E., Tsujimoto I., Horibe T., Tsujimoto Y.;
RT "Functional analysis of human P5, a protein disulfide isomerase
RT homologue.";
RL J. Biochem. 132:451-455(2002).
RN [11]
RP COMPONENT OF A CHAPERONE COMPLEX.
RX PubMed=12475965; DOI=10.1091/mbc.E02-05-0311;
RA Meunier L., Usherwood Y.-K., Chung K.T., Hendershot L.M.;
RT "A subset of chaperones and folding enzymes form multiprotein
RT complexes in endoplasmic reticulum to bind nascent proteins.";
RL Mol. Biol. Cell 13:4456-4469(2002).
RN [12]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [14]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [16]
RP INTERACTION WITH MICA.
RX PubMed=17495932; DOI=10.1038/nature05768;
RA Kaiser B.K., Yim D., Chow I.-T., Gonzalez S., Dai Z., Mann H.H.,
RA Strong R.K., Groh V., Spies T.;
RT "Disulphide-isomerase-enabled shedding of tumour-associated NKG2D
RT ligands.";
RL Nature 447:482-486(2007).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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 [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [24]
RP STRUCTURE BY NMR OF 161-280.
RG RIKEN structural genomics initiative (RSGI);
RT "The solution structure of the second thioredoxin-like domain of human
RT protein disulfide-isomerase A6.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: May function as a chaperone that inhibits aggregation of
CC misfolded proteins. Plays a role in platelet aggregation and
CC activation by agonists such as convulxin, collagen and thrombin.
CC -!- CATALYTIC ACTIVITY: Catalyzes the rearrangement of -S-S- bonds in
CC proteins.
CC -!- SUBUNIT: Part of a large chaperone multiprotein complex comprising
CC DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1,
CC UGT1A1 and very small amounts of ERP29, but not, or at very low
CC levels, CALR nor CANX. Interacts with MICA on the surface of tumor
CC cells, leading to MICA disulfide bond reduction which is required
CC for its release from tumor cells. Interacts with ITGB3 following
CC platelet stimulation.
CC -!- INTERACTION:
CC Q13162:PRDX4; NbExp=2; IntAct=EBI-1043087, EBI-2211957;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen (By similarity).
CC Cell membrane. Melanosome. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15084-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15084-2; Sequence=VSP_021803;
CC -!- TISSUE SPECIFICITY: Expressed in platelets (at protein level).
CC -!- SIMILARITY: Belongs to the protein disulfide isomerase family.
CC -!- SIMILARITY: Contains 2 thioredoxin domains.
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DR EMBL; D49489; BAA08450.1; -; mRNA.
DR EMBL; AK127433; BAC86977.1; -; mRNA.
DR EMBL; AK289428; BAF82117.1; -; mRNA.
DR EMBL; AC092687; AAY24070.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00950.1; -; Genomic_DNA.
DR EMBL; BC001312; AAH01312.1; -; mRNA.
DR EMBL; U79278; AAB50217.1; -; mRNA.
DR PIR; JC4369; JC4369.
DR RefSeq; NP_001269633.1; NM_001282704.1.
DR RefSeq; NP_001269634.1; NM_001282705.1.
DR RefSeq; NP_001269635.1; NM_001282706.1.
DR RefSeq; NP_001269636.1; NM_001282707.1.
DR RefSeq; NP_005733.1; NM_005742.3.
DR UniGene; Hs.212102; -.
DR PDB; 1X5D; NMR; -; A=161-280.
DR PDB; 3VWW; X-ray; 1.93 A; A/B=25-140.
DR PDB; 3W8J; X-ray; 2.10 A; A/B=20-140.
DR PDB; 4EF0; X-ray; 1.50 A; A/B=27-140.
DR PDB; 4GWR; X-ray; 1.81 A; A/B=160-274.
DR PDBsum; 1X5D; -.
DR PDBsum; 3VWW; -.
DR PDBsum; 3W8J; -.
DR PDBsum; 4EF0; -.
DR PDBsum; 4GWR; -.
DR ProteinModelPortal; Q15084; -.
DR SMR; Q15084; 27-280.
DR IntAct; Q15084; 22.
DR MINT; MINT-3030897; -.
DR STRING; 9606.ENSP00000272227; -.
DR ChEMBL; CHEMBL2146308; -.
DR PhosphoSite; Q15084; -.
DR DMDM; 2501205; -.
DR OGP; Q15084; -.
DR REPRODUCTION-2DPAGE; IPI00644989; -.
DR REPRODUCTION-2DPAGE; Q15084; -.
DR PaxDb; Q15084; -.
DR PRIDE; Q15084; -.
DR DNASU; 10130; -.
DR Ensembl; ENST00000272227; ENSP00000272227; ENSG00000143870.
DR Ensembl; ENST00000404371; ENSP00000385385; ENSG00000143870.
DR GeneID; 10130; -.
DR KEGG; hsa:10130; -.
DR UCSC; uc002rau.3; human.
DR CTD; 10130; -.
DR GeneCards; GC02M010923; -.
DR HGNC; HGNC:30168; PDIA6.
DR HPA; HPA034653; -.
DR MIM; 611099; gene.
DR neXtProt; NX_Q15084; -.
DR PharmGKB; PA134977905; -.
DR eggNOG; COG0526; -.
DR HOGENOM; HOG000012631; -.
DR HOVERGEN; HBG053548; -.
DR KO; K09584; -.
DR OMA; KNLEPEW; -.
DR OrthoDB; EOG7XDBFV; -.
DR PhylomeDB; Q15084; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR ChiTaRS; PDIA6; human.
DR EvolutionaryTrace; Q15084; -.
DR GenomeRNAi; 10130; -.
DR NextBio; 38319; -.
DR PRO; PR:Q15084; -.
DR ArrayExpress; Q15084; -.
DR Bgee; Q15084; -.
DR CleanEx; HS_PDIA6; -.
DR Genevestigator; Q15084; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0003756; F:protein disulfide isomerase activity; TAS:ProtInc.
DR GO; GO:0015035; F:protein disulfide oxidoreductase activity; IEA:InterPro.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:0006662; P:glycerol ether metabolic process; IEA:InterPro.
DR Gene3D; 3.40.30.10; -; 2.
DR InterPro; IPR005788; Disulphide_isomerase.
DR InterPro; IPR005746; Thioredoxin.
DR InterPro; IPR012336; Thioredoxin-like_fold.
DR InterPro; IPR017937; Thioredoxin_CS.
DR InterPro; IPR013766; Thioredoxin_domain.
DR Pfam; PF00085; Thioredoxin; 2.
DR PRINTS; PR00421; THIOREDOXIN.
DR SUPFAM; SSF52833; SSF52833; 3.
DR TIGRFAMs; TIGR01126; pdi_dom; 2.
DR PROSITE; PS00014; ER_TARGET; 1.
DR PROSITE; PS00194; THIOREDOXIN_1; 2.
DR PROSITE; PS51352; THIOREDOXIN_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Chaperone;
KW Complete proteome; Direct protein sequencing; Disulfide bond;
KW Endoplasmic reticulum; Isomerase; Membrane; Phosphoprotein;
KW Polymorphism; Redox-active center; Reference proteome; Repeat; Signal.
FT SIGNAL 1 19
FT CHAIN 20 440 Protein disulfide-isomerase A6.
FT /FTId=PRO_0000034236.
FT DOMAIN 20 133 Thioredoxin 1.
FT DOMAIN 154 287 Thioredoxin 2.
FT MOTIF 437 440 Prevents secretion from ER (Potential).
FT COMPBIAS 422 434 Asp/Glu-rich (acidic).
FT ACT_SITE 55 55 Nucleophile (By similarity).
FT ACT_SITE 58 58 Nucleophile (By similarity).
FT ACT_SITE 190 190 Nucleophile (By similarity).
FT ACT_SITE 193 193 Nucleophile (By similarity).
FT SITE 56 56 Contributes to redox potential value (By
FT similarity).
FT SITE 57 57 Contributes to redox potential value (By
FT similarity).
FT SITE 118 118 Lowers pKa of C-terminal Cys of first
FT active site (By similarity).
FT SITE 191 191 Contributes to redox potential value (By
FT similarity).
FT SITE 192 192 Contributes to redox potential value (By
FT similarity).
FT SITE 256 256 Lowers pKa of C-terminal Cys of second
FT active site (By similarity).
FT MOD_RES 428 428 Phosphoserine.
FT DISULFID 55 58 Redox-active (By similarity).
FT DISULFID 190 193 Redox-active (By similarity).
FT VAR_SEQ 1 6 MALLVL -> MRRDLREKLVWVCRPLAPVEVPANISSDFQP
FT CSPTSPAHSLSRKSPIMYPSTTMANAP (in isoform
FT 2).
FT /FTId=VSP_021803.
FT VARIANT 214 214 K -> R (in dbSNP:rs4807).
FT /FTId=VAR_022152.
FT MUTAGEN 55 55 C->S: 50% decrease in enzyme activity;
FT when associated with S-58. Abolishes
FT enzyme activity; when associated with S-
FT 58; S-190 and S-193.
FT MUTAGEN 58 58 C->S: 50% decrease in enzyme activity;
FT when associated with S-55. 90% decrease
FT in enzyme activity; when associated with
FT S-193. Abolishes enzyme activity; when
FT associated with S-55; S-190 and S-193.
FT MUTAGEN 190 190 C->S: 25% decrease in enzyme activity;
FT when associated with S-193. Abolishes
FT enzyme activity; when associated with S-
FT 55; S-58 and S-193.
FT MUTAGEN 193 193 C->S: 90% decrease in enzyme activity;
FT when associated with S-58. 25% decrease
FT in enzyme activity; when associated with
FT S-190. Abolishes enzyme activity; when
FT associated with S-55; S-58 and S-190.
FT STRAND 28 30
FT TURN 32 34
FT HELIX 35 38
FT TURN 39 41
FT STRAND 46 51
FT HELIX 56 71
FT TURN 72 75
FT STRAND 76 82
FT TURN 83 85
FT HELIX 87 92
FT STRAND 100 104
FT STRAND 112 114
FT HELIX 120 139
FT STRAND 162 164
FT TURN 167 169
FT HELIX 170 173
FT TURN 174 176
FT STRAND 178 186
FT HELIX 191 211
FT STRAND 214 221
FT HELIX 222 224
FT HELIX 226 231
FT STRAND 236 243
FT STRAND 247 252
FT HELIX 258 271
SQ SEQUENCE 440 AA; 48121 MW; 06895409F0265D7C CRC64;
MALLVLGLVS CTFFLAVNGL YSSSDDVIEL TPSNFNREVI QSDSLWLVEF YAPWCGHCQR
LTPEWKKAAT ALKDVVKVGA VDADKHHSLG GQYGVQGFPT IKIFGSNKNR PEDYQGGRTG
EAIVDAALSA LRQLVKDRLG GRSGGYSSGK QGRSDSSSKK DVIELTDDSF DKNVLDSEDV
WMVEFYAPWC GHCKNLEPEW AAAASEVKEQ TKGKVKLAAV DATVNQVLAS RYGIRGFPTI
KIFQKGESPV DYDGGRTRSD IVSRALDLFS DNAPPPELLE IINEDIAKRT CEEHQLCVVA
VLPHILDTGA AGRNSYLEVL LKLADKYKKK MWGWLWTEAG AQSELETALG IGGFGYPAMA
AINARKMKFA LLKGSFSEQG INEFLRELSF GRGSTAPVGG GAFPTIVERE PWDGRDGELP
VEDDIDLSDV ELDDLGKDEL
//
ID PDIA6_HUMAN Reviewed; 440 AA.
AC Q15084; Q53RC7; Q6ZSH5; Q99778;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Protein disulfide-isomerase A6;
DE EC=5.3.4.1;
DE AltName: Full=Endoplasmic reticulum protein 5;
DE Short=ER protein 5;
DE Short=ERp5;
DE AltName: Full=Protein disulfide isomerase P5;
DE AltName: Full=Thioredoxin domain-containing protein 7;
DE Flags: Precursor;
GN Name=PDIA6; Synonyms=ERP5, P5, TXNDC7;
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]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=7590364; DOI=10.1016/0378-1119(95)00474-K;
RA Hayano T., Kikuchi M.;
RT "Cloning and sequencing of the cDNA encoding human P5.";
RL Gene 164:377-378(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ARG-214.
RC TISSUE=Thalamus;
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 GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-440 (ISOFORM 1), AND
RP VARIANT ARG-214.
RC TISSUE=Brain;
RX PubMed=9110174;
RA Yu W., Andersson B., Worley K.C., Muzny D.M., Ding Y., Liu W.,
RA Ricafrente J.Y., Wentland M.A., Lennon G., Gibbs R.A.;
RT "Large-scale concatenation cDNA sequencing.";
RL Genome Res. 7:353-358(1997).
RN [7]
RP PROTEIN SEQUENCE [LARGE SCALE ANALYSIS] OF 20-38.
RC TISSUE=Leukemic T-cell;
RX PubMed=19892738; DOI=10.1073/pnas.0908958106;
RA Xu G., Shin S.B., Jaffrey S.R.;
RT "Global profiling of protease cleavage sites by chemoselective
RT labeling of protein N-termini.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:19310-19315(2009).
RN [8]
RP PROTEIN SEQUENCE OF 20-34, FUNCTION, ENZYME ACTIVITY, INTERACTION WITH
RP ITGB3, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15466936; DOI=10.1182/blood-2004-02-0608;
RA Jordan P.A., Stevens J.M., Hubbard G.P., Barrett N.E., Sage T.,
RA Authi K.S., Gibbins J.M.;
RT "A role for the thiol isomerase protein ERP5 in platelet function.";
RL Blood 105:1500-1507(2005).
RN [9]
RP PROTEIN SEQUENCE OF 103-138; 195-212; 217-231; 242-289; 314-328 AND
RP 374-386.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [10]
RP FUNCTION, ENZYME ACTIVITY, AND MUTAGENESIS OF CYS-55; CYS-58; CYS-190
RP AND CYS-193.
RX PubMed=12204115;
RA Kikuchi M., Doi E., Tsujimoto I., Horibe T., Tsujimoto Y.;
RT "Functional analysis of human P5, a protein disulfide isomerase
RT homologue.";
RL J. Biochem. 132:451-455(2002).
RN [11]
RP COMPONENT OF A CHAPERONE COMPLEX.
RX PubMed=12475965; DOI=10.1091/mbc.E02-05-0311;
RA Meunier L., Usherwood Y.-K., Chung K.T., Hendershot L.M.;
RT "A subset of chaperones and folding enzymes form multiprotein
RT complexes in endoplasmic reticulum to bind nascent proteins.";
RL Mol. Biol. Cell 13:4456-4469(2002).
RN [12]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [14]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [16]
RP INTERACTION WITH MICA.
RX PubMed=17495932; DOI=10.1038/nature05768;
RA Kaiser B.K., Yim D., Chow I.-T., Gonzalez S., Dai Z., Mann H.H.,
RA Strong R.K., Groh V., Spies T.;
RT "Disulphide-isomerase-enabled shedding of tumour-associated NKG2D
RT ligands.";
RL Nature 447:482-486(2007).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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 [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [24]
RP STRUCTURE BY NMR OF 161-280.
RG RIKEN structural genomics initiative (RSGI);
RT "The solution structure of the second thioredoxin-like domain of human
RT protein disulfide-isomerase A6.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: May function as a chaperone that inhibits aggregation of
CC misfolded proteins. Plays a role in platelet aggregation and
CC activation by agonists such as convulxin, collagen and thrombin.
CC -!- CATALYTIC ACTIVITY: Catalyzes the rearrangement of -S-S- bonds in
CC proteins.
CC -!- SUBUNIT: Part of a large chaperone multiprotein complex comprising
CC DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1,
CC UGT1A1 and very small amounts of ERP29, but not, or at very low
CC levels, CALR nor CANX. Interacts with MICA on the surface of tumor
CC cells, leading to MICA disulfide bond reduction which is required
CC for its release from tumor cells. Interacts with ITGB3 following
CC platelet stimulation.
CC -!- INTERACTION:
CC Q13162:PRDX4; NbExp=2; IntAct=EBI-1043087, EBI-2211957;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen (By similarity).
CC Cell membrane. Melanosome. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15084-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15084-2; Sequence=VSP_021803;
CC -!- TISSUE SPECIFICITY: Expressed in platelets (at protein level).
CC -!- SIMILARITY: Belongs to the protein disulfide isomerase family.
CC -!- SIMILARITY: Contains 2 thioredoxin domains.
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DR EMBL; D49489; BAA08450.1; -; mRNA.
DR EMBL; AK127433; BAC86977.1; -; mRNA.
DR EMBL; AK289428; BAF82117.1; -; mRNA.
DR EMBL; AC092687; AAY24070.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00950.1; -; Genomic_DNA.
DR EMBL; BC001312; AAH01312.1; -; mRNA.
DR EMBL; U79278; AAB50217.1; -; mRNA.
DR PIR; JC4369; JC4369.
DR RefSeq; NP_001269633.1; NM_001282704.1.
DR RefSeq; NP_001269634.1; NM_001282705.1.
DR RefSeq; NP_001269635.1; NM_001282706.1.
DR RefSeq; NP_001269636.1; NM_001282707.1.
DR RefSeq; NP_005733.1; NM_005742.3.
DR UniGene; Hs.212102; -.
DR PDB; 1X5D; NMR; -; A=161-280.
DR PDB; 3VWW; X-ray; 1.93 A; A/B=25-140.
DR PDB; 3W8J; X-ray; 2.10 A; A/B=20-140.
DR PDB; 4EF0; X-ray; 1.50 A; A/B=27-140.
DR PDB; 4GWR; X-ray; 1.81 A; A/B=160-274.
DR PDBsum; 1X5D; -.
DR PDBsum; 3VWW; -.
DR PDBsum; 3W8J; -.
DR PDBsum; 4EF0; -.
DR PDBsum; 4GWR; -.
DR ProteinModelPortal; Q15084; -.
DR SMR; Q15084; 27-280.
DR IntAct; Q15084; 22.
DR MINT; MINT-3030897; -.
DR STRING; 9606.ENSP00000272227; -.
DR ChEMBL; CHEMBL2146308; -.
DR PhosphoSite; Q15084; -.
DR DMDM; 2501205; -.
DR OGP; Q15084; -.
DR REPRODUCTION-2DPAGE; IPI00644989; -.
DR REPRODUCTION-2DPAGE; Q15084; -.
DR PaxDb; Q15084; -.
DR PRIDE; Q15084; -.
DR DNASU; 10130; -.
DR Ensembl; ENST00000272227; ENSP00000272227; ENSG00000143870.
DR Ensembl; ENST00000404371; ENSP00000385385; ENSG00000143870.
DR GeneID; 10130; -.
DR KEGG; hsa:10130; -.
DR UCSC; uc002rau.3; human.
DR CTD; 10130; -.
DR GeneCards; GC02M010923; -.
DR HGNC; HGNC:30168; PDIA6.
DR HPA; HPA034653; -.
DR MIM; 611099; gene.
DR neXtProt; NX_Q15084; -.
DR PharmGKB; PA134977905; -.
DR eggNOG; COG0526; -.
DR HOGENOM; HOG000012631; -.
DR HOVERGEN; HBG053548; -.
DR KO; K09584; -.
DR OMA; KNLEPEW; -.
DR OrthoDB; EOG7XDBFV; -.
DR PhylomeDB; Q15084; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR ChiTaRS; PDIA6; human.
DR EvolutionaryTrace; Q15084; -.
DR GenomeRNAi; 10130; -.
DR NextBio; 38319; -.
DR PRO; PR:Q15084; -.
DR ArrayExpress; Q15084; -.
DR Bgee; Q15084; -.
DR CleanEx; HS_PDIA6; -.
DR Genevestigator; Q15084; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0003756; F:protein disulfide isomerase activity; TAS:ProtInc.
DR GO; GO:0015035; F:protein disulfide oxidoreductase activity; IEA:InterPro.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:0006662; P:glycerol ether metabolic process; IEA:InterPro.
DR Gene3D; 3.40.30.10; -; 2.
DR InterPro; IPR005788; Disulphide_isomerase.
DR InterPro; IPR005746; Thioredoxin.
DR InterPro; IPR012336; Thioredoxin-like_fold.
DR InterPro; IPR017937; Thioredoxin_CS.
DR InterPro; IPR013766; Thioredoxin_domain.
DR Pfam; PF00085; Thioredoxin; 2.
DR PRINTS; PR00421; THIOREDOXIN.
DR SUPFAM; SSF52833; SSF52833; 3.
DR TIGRFAMs; TIGR01126; pdi_dom; 2.
DR PROSITE; PS00014; ER_TARGET; 1.
DR PROSITE; PS00194; THIOREDOXIN_1; 2.
DR PROSITE; PS51352; THIOREDOXIN_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Chaperone;
KW Complete proteome; Direct protein sequencing; Disulfide bond;
KW Endoplasmic reticulum; Isomerase; Membrane; Phosphoprotein;
KW Polymorphism; Redox-active center; Reference proteome; Repeat; Signal.
FT SIGNAL 1 19
FT CHAIN 20 440 Protein disulfide-isomerase A6.
FT /FTId=PRO_0000034236.
FT DOMAIN 20 133 Thioredoxin 1.
FT DOMAIN 154 287 Thioredoxin 2.
FT MOTIF 437 440 Prevents secretion from ER (Potential).
FT COMPBIAS 422 434 Asp/Glu-rich (acidic).
FT ACT_SITE 55 55 Nucleophile (By similarity).
FT ACT_SITE 58 58 Nucleophile (By similarity).
FT ACT_SITE 190 190 Nucleophile (By similarity).
FT ACT_SITE 193 193 Nucleophile (By similarity).
FT SITE 56 56 Contributes to redox potential value (By
FT similarity).
FT SITE 57 57 Contributes to redox potential value (By
FT similarity).
FT SITE 118 118 Lowers pKa of C-terminal Cys of first
FT active site (By similarity).
FT SITE 191 191 Contributes to redox potential value (By
FT similarity).
FT SITE 192 192 Contributes to redox potential value (By
FT similarity).
FT SITE 256 256 Lowers pKa of C-terminal Cys of second
FT active site (By similarity).
FT MOD_RES 428 428 Phosphoserine.
FT DISULFID 55 58 Redox-active (By similarity).
FT DISULFID 190 193 Redox-active (By similarity).
FT VAR_SEQ 1 6 MALLVL -> MRRDLREKLVWVCRPLAPVEVPANISSDFQP
FT CSPTSPAHSLSRKSPIMYPSTTMANAP (in isoform
FT 2).
FT /FTId=VSP_021803.
FT VARIANT 214 214 K -> R (in dbSNP:rs4807).
FT /FTId=VAR_022152.
FT MUTAGEN 55 55 C->S: 50% decrease in enzyme activity;
FT when associated with S-58. Abolishes
FT enzyme activity; when associated with S-
FT 58; S-190 and S-193.
FT MUTAGEN 58 58 C->S: 50% decrease in enzyme activity;
FT when associated with S-55. 90% decrease
FT in enzyme activity; when associated with
FT S-193. Abolishes enzyme activity; when
FT associated with S-55; S-190 and S-193.
FT MUTAGEN 190 190 C->S: 25% decrease in enzyme activity;
FT when associated with S-193. Abolishes
FT enzyme activity; when associated with S-
FT 55; S-58 and S-193.
FT MUTAGEN 193 193 C->S: 90% decrease in enzyme activity;
FT when associated with S-58. 25% decrease
FT in enzyme activity; when associated with
FT S-190. Abolishes enzyme activity; when
FT associated with S-55; S-58 and S-190.
FT STRAND 28 30
FT TURN 32 34
FT HELIX 35 38
FT TURN 39 41
FT STRAND 46 51
FT HELIX 56 71
FT TURN 72 75
FT STRAND 76 82
FT TURN 83 85
FT HELIX 87 92
FT STRAND 100 104
FT STRAND 112 114
FT HELIX 120 139
FT STRAND 162 164
FT TURN 167 169
FT HELIX 170 173
FT TURN 174 176
FT STRAND 178 186
FT HELIX 191 211
FT STRAND 214 221
FT HELIX 222 224
FT HELIX 226 231
FT STRAND 236 243
FT STRAND 247 252
FT HELIX 258 271
SQ SEQUENCE 440 AA; 48121 MW; 06895409F0265D7C CRC64;
MALLVLGLVS CTFFLAVNGL YSSSDDVIEL TPSNFNREVI QSDSLWLVEF YAPWCGHCQR
LTPEWKKAAT ALKDVVKVGA VDADKHHSLG GQYGVQGFPT IKIFGSNKNR PEDYQGGRTG
EAIVDAALSA LRQLVKDRLG GRSGGYSSGK QGRSDSSSKK DVIELTDDSF DKNVLDSEDV
WMVEFYAPWC GHCKNLEPEW AAAASEVKEQ TKGKVKLAAV DATVNQVLAS RYGIRGFPTI
KIFQKGESPV DYDGGRTRSD IVSRALDLFS DNAPPPELLE IINEDIAKRT CEEHQLCVVA
VLPHILDTGA AGRNSYLEVL LKLADKYKKK MWGWLWTEAG AQSELETALG IGGFGYPAMA
AINARKMKFA LLKGSFSEQG INEFLRELSF GRGSTAPVGG GAFPTIVERE PWDGRDGELP
VEDDIDLSDV ELDDLGKDEL
//
MIM
611099
*RECORD*
*FIELD* NO
611099
*FIELD* TI
*611099 PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 6; PDIA6
;;P5;;
ENDOPLASMIC RETICULUM PROTEIN 5; ERP5
read more*FIELD* TX
DESCRIPTION
Protein disulfide isomerases (EC 5.3.4.1), such as PDIA6, are
endoplasmic reticulum (ER) resident proteins that catalyze formation,
reduction, and isomerization of disulfide bonds in proteins and are
thought to play a role in folding of disulfide-bonded proteins (Hayano
and Kikuchi, 1995).
CLONING
By screening a placenta cDNA library with a PDI (P4HB; 176790) cDNA
fragment, Hayano and Kikuchi (1995) cloned PDIA6, which they called P5.
The deduced 440-amino acid protein has a calculated molecular mass of
48.1 kD. It has a putative N-terminal signal sequence, followed by 2
thioredoxin (TXN; 187700)-like domains and a C-terminal ER retention
signal (KDEL).
Chaudhuri et al. (1992) found that mouse P5 showed highest expression in
lung, with progressively lower levels in kidney, heart, liver, and
brain.
GENE FUNCTION
Chaudhuri et al. (1992) showed that P5, Rrm2 (180410), and Odc1 (154640)
were coamplified in hamster cells resistant to hydroxyurea, a potent
inhibitor of ribonucleotide reductase. Since P5, RRM2, and ODC1 are
closely linked in the hamster and human genomes, Chaudhuri et al. (1992)
hypothesized that they may form an amplicon.
Kikuchi et al. (2002) found that recombinant human P5 had both isomerase
and chaperone activities, but both activities were lower than those of
human PDI. P5 showed peptide-binding activity, and its chaperone
activity appeared to be substrate specific. Mutation analysis revealed
that the first thioredoxin-like motif of P5 was more important than the
second for isomerase activity, and that the first cysteine in each motif
was necessary for isomerase activity. Thioredoxin motif mutants of P5
lacking isomerase activity retained chaperone activity with citrate
synthase (CS; 118950) as substrate, indicating that, like PDI, the
isomerase and chaperone activities of P5 are likely independent.
Kaiser et al. (2007) showed that on the surface of tumor cells, MICA
(600169) associates with ERP5, which, similar to protein disulfide
isomerase (176790), usually assists in the folding of nascent proteins
inside cells. Pharmacologic inhibition of thioreductase activity and
ERP5 gene silencing revealed that cell-surface ERP5 function is required
for MICA shedding. ERP5 and membrane-anchored MICA formed transitory
mixed disulfide complexes from which soluble MICA was released after
proteolytic cleavage near the cell membrane. Kaiser et al. (2007)
suggested that reduction of the seemingly inaccessible disulfide bond in
the membrane-proximal alpha-3 domain of MICA must involve a large
conformational change that enables proteolytic cleavage. They concluded
that their results uncovered a molecular mechanism whereby
domain-specific deconstruction regulates MICA protein shedding, thereby
promoting tumor immune evasion, and identified surface ERP5 as a
strategic target for therapeutic intervention.
MAPPING
By in situ hybridization, Yang-Feng et al. (1987) mapped the PDIA6 gene
to chromosome 2p25-p24.
ANIMAL MODEL
The zebrafish 'one-eyed pinhead' (oep) mutation is characterized by
multiple deficiencies in midline development and a morphologically
normal notochord. Hoshijima et al. (2002) found that P5 was expressed
predominantly in the axial mesoderm of midgastrula wildtype embryos and
was significantly downregulated in oep mutants. Functional analysis
demonstrated that P5 was specifically involved in lateral patterning.
Depletion of P5 protein with antisense morpholino oligonucleotides
revealed that P5 was required to establish asymmetric gene expression in
the lateral plate mesoderm and brain and for regulating morphologic
asymmetries in development of the heart, liver, and pancreas.
Interference with P5 function did not perturb other aspects of midline
development or function.
*FIELD* RF
1. Chaudhuri, M. M.; Tonin, P. N.; Lewis, W. H.; Srinivasan, P. R.
: The gene for a novel protein, a member of the protein disulphide
isomerase/Form I phosphoinositide-specific phospholipase C family,
is amplified in hydroxyurea-resistant cells. Biochem. J. 281: 645-650,
1992.
2. Hayano, T.; Kikuchi, M.: Cloning and sequencing of the cDNA encoding
human P5. Gene 164: 377-378, 1995.
3. Hoshijima, K.; Metherall, J. E.; Grunwald, D. J.: A protein disulfide
isomerase expressed in the embryonic midline is required for left/right
asymmetries. Genes Dev. 16: 2518-2529, 2002.
4. Kaiser, B. K.; Yim, D.; Chow, I.-T.; Gonzalez, S.; Dai, Z.; Mann,
H. H.; Strong, R. K.; Groh, V.; Spies, T.: Disulphide-isomerase-enabled
structure of tumour-associated NKG2D ligands. Nature 447: 482-486,
2007.
5. Kikuchi, M.; Doi, E.; Tsujimoto, I.; Horibe, T.; Tsujimoto, Y.
: Functional analysis of human P5, a protein disulfide isomerase homologue. J.
Biochem. 132: 451-455, 2002.
6. Yang-Feng, T. L.; Barton, D. E.; Thelander, L.; Lewis, W. H.; Srinivasan,
P. R.; Francke, U.: Ribonucleotide reductase M2 subunit sequences
mapped to four different chromosomal sites in humans and mice: functional
locus identified by its amplification in hydroxyurea-resistant cell
lines. Genomics 1: 77-86, 1987.
*FIELD* CN
Ada Hamosh - updated: 6/28/2007
*FIELD* CD
Patricia A. Hartz: 6/7/2007
*FIELD* ED
carol: 09/12/2007
alopez: 6/28/2007
mgross: 6/7/2007
*RECORD*
*FIELD* NO
611099
*FIELD* TI
*611099 PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 6; PDIA6
;;P5;;
ENDOPLASMIC RETICULUM PROTEIN 5; ERP5
read more*FIELD* TX
DESCRIPTION
Protein disulfide isomerases (EC 5.3.4.1), such as PDIA6, are
endoplasmic reticulum (ER) resident proteins that catalyze formation,
reduction, and isomerization of disulfide bonds in proteins and are
thought to play a role in folding of disulfide-bonded proteins (Hayano
and Kikuchi, 1995).
CLONING
By screening a placenta cDNA library with a PDI (P4HB; 176790) cDNA
fragment, Hayano and Kikuchi (1995) cloned PDIA6, which they called P5.
The deduced 440-amino acid protein has a calculated molecular mass of
48.1 kD. It has a putative N-terminal signal sequence, followed by 2
thioredoxin (TXN; 187700)-like domains and a C-terminal ER retention
signal (KDEL).
Chaudhuri et al. (1992) found that mouse P5 showed highest expression in
lung, with progressively lower levels in kidney, heart, liver, and
brain.
GENE FUNCTION
Chaudhuri et al. (1992) showed that P5, Rrm2 (180410), and Odc1 (154640)
were coamplified in hamster cells resistant to hydroxyurea, a potent
inhibitor of ribonucleotide reductase. Since P5, RRM2, and ODC1 are
closely linked in the hamster and human genomes, Chaudhuri et al. (1992)
hypothesized that they may form an amplicon.
Kikuchi et al. (2002) found that recombinant human P5 had both isomerase
and chaperone activities, but both activities were lower than those of
human PDI. P5 showed peptide-binding activity, and its chaperone
activity appeared to be substrate specific. Mutation analysis revealed
that the first thioredoxin-like motif of P5 was more important than the
second for isomerase activity, and that the first cysteine in each motif
was necessary for isomerase activity. Thioredoxin motif mutants of P5
lacking isomerase activity retained chaperone activity with citrate
synthase (CS; 118950) as substrate, indicating that, like PDI, the
isomerase and chaperone activities of P5 are likely independent.
Kaiser et al. (2007) showed that on the surface of tumor cells, MICA
(600169) associates with ERP5, which, similar to protein disulfide
isomerase (176790), usually assists in the folding of nascent proteins
inside cells. Pharmacologic inhibition of thioreductase activity and
ERP5 gene silencing revealed that cell-surface ERP5 function is required
for MICA shedding. ERP5 and membrane-anchored MICA formed transitory
mixed disulfide complexes from which soluble MICA was released after
proteolytic cleavage near the cell membrane. Kaiser et al. (2007)
suggested that reduction of the seemingly inaccessible disulfide bond in
the membrane-proximal alpha-3 domain of MICA must involve a large
conformational change that enables proteolytic cleavage. They concluded
that their results uncovered a molecular mechanism whereby
domain-specific deconstruction regulates MICA protein shedding, thereby
promoting tumor immune evasion, and identified surface ERP5 as a
strategic target for therapeutic intervention.
MAPPING
By in situ hybridization, Yang-Feng et al. (1987) mapped the PDIA6 gene
to chromosome 2p25-p24.
ANIMAL MODEL
The zebrafish 'one-eyed pinhead' (oep) mutation is characterized by
multiple deficiencies in midline development and a morphologically
normal notochord. Hoshijima et al. (2002) found that P5 was expressed
predominantly in the axial mesoderm of midgastrula wildtype embryos and
was significantly downregulated in oep mutants. Functional analysis
demonstrated that P5 was specifically involved in lateral patterning.
Depletion of P5 protein with antisense morpholino oligonucleotides
revealed that P5 was required to establish asymmetric gene expression in
the lateral plate mesoderm and brain and for regulating morphologic
asymmetries in development of the heart, liver, and pancreas.
Interference with P5 function did not perturb other aspects of midline
development or function.
*FIELD* RF
1. Chaudhuri, M. M.; Tonin, P. N.; Lewis, W. H.; Srinivasan, P. R.
: The gene for a novel protein, a member of the protein disulphide
isomerase/Form I phosphoinositide-specific phospholipase C family,
is amplified in hydroxyurea-resistant cells. Biochem. J. 281: 645-650,
1992.
2. Hayano, T.; Kikuchi, M.: Cloning and sequencing of the cDNA encoding
human P5. Gene 164: 377-378, 1995.
3. Hoshijima, K.; Metherall, J. E.; Grunwald, D. J.: A protein disulfide
isomerase expressed in the embryonic midline is required for left/right
asymmetries. Genes Dev. 16: 2518-2529, 2002.
4. Kaiser, B. K.; Yim, D.; Chow, I.-T.; Gonzalez, S.; Dai, Z.; Mann,
H. H.; Strong, R. K.; Groh, V.; Spies, T.: Disulphide-isomerase-enabled
structure of tumour-associated NKG2D ligands. Nature 447: 482-486,
2007.
5. Kikuchi, M.; Doi, E.; Tsujimoto, I.; Horibe, T.; Tsujimoto, Y.
: Functional analysis of human P5, a protein disulfide isomerase homologue. J.
Biochem. 132: 451-455, 2002.
6. Yang-Feng, T. L.; Barton, D. E.; Thelander, L.; Lewis, W. H.; Srinivasan,
P. R.; Francke, U.: Ribonucleotide reductase M2 subunit sequences
mapped to four different chromosomal sites in humans and mice: functional
locus identified by its amplification in hydroxyurea-resistant cell
lines. Genomics 1: 77-86, 1987.
*FIELD* CN
Ada Hamosh - updated: 6/28/2007
*FIELD* CD
Patricia A. Hartz: 6/7/2007
*FIELD* ED
carol: 09/12/2007
alopez: 6/28/2007
mgross: 6/7/2007