ID   PDIA1_RAT               Reviewed;         509 AA.
AC   P04785; P13700;
DT   13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1989, sequence version 2.
DT   27-MAR-2024, entry version 209.
DE   RecName: Full=Protein disulfide-isomerase;
DE            Short=PDI;
DE            EC=5.3.4.1 {ECO:0000250|UniProtKB:P07237};
DE   AltName: Full=Cellular thyroid hormone-binding protein;
DE   AltName: Full=Prolyl 4-hydroxylase subunit beta;
DE   Flags: Precursor;
GN   Name=P4hb; Synonyms=Pdia1;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=3840230; DOI=10.1038/317267a0;
RA   Edman J.C., Ellis L., Blacher R.W., Roth R.A., Rutter W.J.;
RT   "Sequence of protein disulphide isomerase and implications of its
RT   relationship to thioredoxin.";
RL   Nature 317:267-270(1985).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Prostate;
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   [3]
RP   PROTEIN SEQUENCE OF 20-34.
RC   STRAIN=LEC; TISSUE=Liver;
RX   PubMed=8251535; DOI=10.1016/0304-4165(93)90033-5;
RA   Yokoi T., Nagayama S., Kajiwara R., Kawaguchi Y., Horiuchi R., Kamataki T.;
RT   "Identification of protein disulfide isomerase and calreticulin as
RT   autoimmune antigens in LEC strain of rats.";
RL   Biochim. Biophys. Acta 1158:339-344(1993).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 28-509.
RC   TISSUE=Liver;
RX   PubMed=3178809; DOI=10.1016/s0006-291x(88)81282-8;
RA   Boado R.J., Campbell D.A., Chopra I.J.;
RT   "Nucleotide sequence of rat liver iodothyronine 5'-monodeiodinase (5' MD):
RT   its identity with the protein disulfide isomerase.";
RL   Biochem. Biophys. Res. Commun. 155:1297-1304(1988).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 129-394.
RC   TISSUE=Liver;
RX   PubMed=2841089; DOI=10.1210/endo-123-3-1264;
RA   Boado R.J., Chopra I.J., Flink I.L., Campbell D.A.;
RT   "Enzyme binding-inhibiting assay for iodothyronine 5'-monodeiodinase (5'-
RT   MD) and its application to isolation of complementary deoxyribonucleic acid
RT   clones for the 5'-MD in rat liver.";
RL   Endocrinology 123:1264-1273(1988).
RN   [6]
RP   PROTEIN SEQUENCE OF 233-249; 288-302 AND 341-352, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY.
RC   STRAIN=Sprague-Dawley; TISSUE=Hippocampus, and Spinal cord;
RA   Lubec G., Afjehi-Sadat L., Chen W.-Q.;
RL   Submitted (APR-2007) to UniProtKB.
RN   [7]
RP   PROTEIN SEQUENCE OF 471-494.
RX   PubMed=8366073; DOI=10.1016/s0021-9258(19)36501-9;
RA   Noiva R., Freedman R.B., Lennarz W.J.;
RT   "Peptide binding to protein disulfide isomerase occurs at a site distinct
RT   from the active sites.";
RL   J. Biol. Chem. 268:19210-19217(1993).
RN   [8]
RP   SHOWS THAT PROTEIN IS NOT IDENTICAL TO THYROXINE DEIODINASE.
RX   PubMed=2757644; DOI=10.1016/0006-291x(89)92389-9;
RA   Schoenmakers C.H.H., Pigmans I.G.A.J., Hawkins H.C., Freedman R.B.,
RA   Visser T.J.;
RT   "Rat liver type I iodothyronine deiodinase is not identical to protein
RT   disulfide isomerase.";
RL   Biochem. Biophys. Res. Commun. 162:857-868(1989).
CC   -!- FUNCTION: This multifunctional protein catalyzes the formation,
CC       breakage and rearrangement of disulfide bonds. At the cell surface,
CC       seems to act as a reductase that cleaves disulfide bonds of proteins
CC       attached to the cell. May therefore cause structural modifications of
CC       exofacial proteins. Inside the cell, seems to form/rearrange disulfide
CC       bonds of nascent proteins. At high concentrations and following
CC       phosphorylation by FAM20C, functions as a chaperone that inhibits
CC       aggregation of misfolded proteins. At low concentrations, facilitates
CC       aggregation (anti-chaperone activity). May be involved with other
CC       chaperones in the structural modification of the TG precursor in
CC       hormone biogenesis. Also acts as a structural subunit of various
CC       enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol
CC       transfer protein MTTP. Receptor for LGALS9; the interaction retains
CC       P4HB at the cell surface of Th2 T helper cells, increasing disulfide
CC       reductase activity at the plasma membrane, altering the plasma membrane
CC       redox state and enhancing cell migration.
CC       {ECO:0000250|UniProtKB:P07237}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Catalyzes the rearrangement of -S-S- bonds in proteins.;
CC         EC=5.3.4.1; Evidence={ECO:0000250|UniProtKB:P07237};
CC   -!- SUBUNIT: Heterodimer; heterodimerizes with the protein microsomal
CC       triglyceride transfer MTTP. Homodimer. Monomers and homotetramers may
CC       also occur. Interacts with P4HA2, forming a heterotetramer consisting
CC       of 2 alpha subunits (P4HA2) and 2 beta (P4HB), where P4HB plays the
CC       role of a structural subunit; this tetramer catalyzes the formation of
CC       4-hydroxyproline in collagen (By similarity). Also constitutes the
CC       structural subunit of the microsomal triacylglycerol transfer protein
CC       MTTP in mammalian cells. Stabilizes both enzymes and retain them in the
CC       ER without contributing to the catalytic activity. Binds UBQLN1.
CC       Interacts with ERO1B. Interacts with ILDR2 (By similarity). Interacts
CC       with ERN1/IRE1A (via N-terminus); the interaction is enhanced by
CC       phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum
CC       stress and results in attenuation of ERN1 activity (By similarity).
CC       {ECO:0000250, ECO:0000250|UniProtKB:P07237,
CC       ECO:0000250|UniProtKB:P09103}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC       {ECO:0000250|UniProtKB:P07237}. Endoplasmic reticulum lumen
CC       {ECO:0000250|UniProtKB:P07237}. Melanosome
CC       {ECO:0000250|UniProtKB:P07237}. Cell membrane
CC       {ECO:0000250|UniProtKB:P09103}; Peripheral membrane protein
CC       {ECO:0000305}. Note=Highly abundant. In some cell types, seems to be
CC       also secreted or associated with the plasma membrane, where it
CC       undergoes constant shedding and replacement from intracellular sources.
CC       Localizes near CD4-enriched regions on lymphoid cell surfaces.
CC       Colocalizes with MTTP in the endoplasmic reticulum.
CC       {ECO:0000250|UniProtKB:P07237}.
CC   -!- PTM: Phosphorylation of Ser-359 by FAM20C is induced by endoplasmic
CC       reticulum stress and results in a functional switch from oxidoreductase
CC       to molecular chaperone. It also promotes interaction with ERN1.
CC       {ECO:0000250|UniProtKB:P07237}.
CC   -!- SIMILARITY: Belongs to the protein disulfide isomerase family.
CC       {ECO:0000305}.
CC   -!- CAUTION: Was originally (PubMed:8251535, PubMed:3178809) thought to be
CC       identical to thyroxine deiodinase but this was later shown to be
CC       incorrect. {ECO:0000305|PubMed:2757644}.
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DR   EMBL; M21018; AAA40620.1; -; mRNA.
DR   EMBL; BC061857; AAH61857.1; -; mRNA.
DR   EMBL; X02918; CAA26675.1; -; mRNA.
DR   EMBL; M21476; AAA40619.1; -; mRNA.
DR   PIR; A24595; ISRTSS.
DR   PIR; S68028; S68028.
DR   RefSeq; NP_037130.2; NM_012998.2.
DR   AlphaFoldDB; P04785; -.
DR   SMR; P04785; -.
DR   BioGRID; 247538; 3.
DR   IntAct; P04785; 8.
DR   MINT; P04785; -.
DR   STRING; 10116.ENSRNOP00000051841; -.
DR   GlyGen; P04785; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P04785; -.
DR   PhosphoSitePlus; P04785; -.
DR   jPOST; P04785; -.
DR   PaxDb; 10116-ENSRNOP00000051841; -.
DR   Ensembl; ENSRNOT00000054958.3; ENSRNOP00000051841.1; ENSRNOG00000036689.3.
DR   Ensembl; ENSRNOT00055056725; ENSRNOP00055046830; ENSRNOG00055032801.
DR   Ensembl; ENSRNOT00060053755; ENSRNOP00060044619; ENSRNOG00060030940.
DR   Ensembl; ENSRNOT00065005811; ENSRNOP00065004180; ENSRNOG00065003976.
DR   GeneID; 25506; -.
DR   KEGG; rno:25506; -.
DR   AGR; RGD:3244; -.
DR   CTD; 5034; -.
DR   RGD; 3244; P4hb.
DR   eggNOG; KOG0190; Eukaryota.
DR   GeneTree; ENSGT00940000157351; -.
DR   HOGENOM; CLU_025879_1_0_1; -.
DR   InParanoid; P04785; -.
DR   OMA; FFGMKKD; -.
DR   OrthoDB; 5399045at2759; -.
DR   PhylomeDB; P04785; -.
DR   TreeFam; TF106381; -.
DR   BRENDA; 5.3.4.1; 5301.
DR   Reactome; R-RNO-1650814; Collagen biosynthesis and modifying enzymes.
DR   Reactome; R-RNO-264876; Insulin processing.
DR   Reactome; R-RNO-3299685; Detoxification of Reactive Oxygen Species.
DR   Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   Reactome; R-RNO-5358346; Hedgehog ligand biogenesis.
DR   Reactome; R-RNO-8866423; VLDL assembly.
DR   Reactome; R-RNO-8957275; Post-translational protein phosphorylation.
DR   Reactome; R-RNO-8963888; Chylomicron assembly.
DR   Reactome; R-RNO-8964041; LDL remodeling.
DR   Reactome; R-RNO-9020591; Interleukin-12 signaling.
DR   Reactome; R-RNO-9020933; Interleukin-23 signaling.
DR   PRO; PR:P04785; -.
DR   Proteomes; UP000002494; Chromosome 10.
DR   Bgee; ENSRNOG00000036689; Expressed in jejunum and 20 other cell types or tissues.
DR   GO; GO:0005856; C:cytoskeleton; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; ISO:RGD.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0034663; C:endoplasmic reticulum chaperone complex; ISO:RGD.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; ISO:RGD.
DR   GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; ISO:RGD.
DR   GO; GO:0009897; C:external side of plasma membrane; ISO:RGD.
DR   GO; GO:0030027; C:lamellipodium; ISO:RGD.
DR   GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0016222; C:procollagen-proline 4-dioxygenase complex; ISO:RGD.
DR   GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR   GO; GO:0003779; F:actin binding; ISO:RGD.
DR   GO; GO:0019899; F:enzyme binding; IPI:RGD.
DR   GO; GO:0005178; F:integrin binding; ISO:RGD.
DR   GO; GO:0004656; F:procollagen-proline 4-dioxygenase activity; IEA:Ensembl.
DR   GO; GO:0003756; F:protein disulfide isomerase activity; IMP:RGD.
DR   GO; GO:0046982; F:protein heterodimerization activity; ISO:RGD.
DR   GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
DR   GO; GO:0015035; F:protein-disulfide reductase activity; ISO:RGD.
DR   GO; GO:0016972; F:thiol oxidase activity; ISO:RGD.
DR   GO; GO:0071456; P:cellular response to hypoxia; ISO:RGD.
DR   GO; GO:0098761; P:cellular response to interleukin-7; ISO:RGD.
DR   GO; GO:0006888; P:endoplasmic reticulum to Golgi vesicle-mediated transport; ISO:RGD.
DR   GO; GO:0030070; P:insulin processing; ISO:RGD.
DR   GO; GO:0045785; P:positive regulation of cell adhesion; ISO:RGD.
DR   GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; ISO:RGD.
DR   GO; GO:0046598; P:positive regulation of viral entry into host cell; ISO:RGD.
DR   GO; GO:0006457; P:protein folding; IBA:GO_Central.
DR   GO; GO:0034975; P:protein folding in endoplasmic reticulum; ISO:RGD.
DR   GO; GO:1902175; P:regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; ISO:RGD.
DR   GO; GO:0034976; P:response to endoplasmic reticulum stress; ISO:RGD.
DR   CDD; cd02961; PDI_a_family; 1.
DR   CDD; cd02995; PDI_a_PDI_a'_C; 1.
DR   CDD; cd02982; PDI_b'_family; 1.
DR   CDD; cd02981; PDI_b_family; 1.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 4.
DR   InterPro; IPR005788; PDI_thioredoxin-like_dom.
DR   InterPro; IPR005792; Prot_disulphide_isomerase.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   InterPro; IPR017937; Thioredoxin_CS.
DR   InterPro; IPR013766; Thioredoxin_domain.
DR   NCBIfam; TIGR01130; ER_PDI_fam; 1.
DR   NCBIfam; TIGR01126; pdi_dom; 2.
DR   PANTHER; PTHR18929; PROTEIN DISULFIDE ISOMERASE; 1.
DR   PANTHER; PTHR18929:SF101; PROTEIN DISULFIDE-ISOMERASE; 1.
DR   Pfam; PF00085; Thioredoxin; 2.
DR   Pfam; PF13848; Thioredoxin_6; 1.
DR   PRINTS; PR00421; THIOREDOXIN.
DR   SUPFAM; SSF52833; Thioredoxin-like; 4.
DR   PROSITE; PS00014; ER_TARGET; 1.
DR   PROSITE; PS00194; THIOREDOXIN_1; 2.
DR   PROSITE; PS51352; THIOREDOXIN_2; 2.
DR   Genevisible; P04785; RN.
PE   1: Evidence at protein level;
KW   Acetylation; Cell membrane; Chaperone; Direct protein sequencing;
KW   Disulfide bond; Endoplasmic reticulum; Isomerase; Membrane; Phosphoprotein;
KW   Redox-active center; Reference proteome; Repeat; Signal.
FT   SIGNAL          1..19
FT                   /evidence="ECO:0000269|PubMed:8251535"
FT   CHAIN           20..509
FT                   /note="Protein disulfide-isomerase"
FT                   /id="PRO_0000034199"
FT   DOMAIN          20..136
FT                   /note="Thioredoxin 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT   DOMAIN          335..477
FT                   /note="Thioredoxin 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT   MOTIF           506..509
FT                   /note="Prevents secretion from ER"
FT   ACT_SITE        55
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        58
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        399
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        402
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   SITE            56
FT                   /note="Contributes to redox potential value"
FT                   /evidence="ECO:0000250"
FT   SITE            57
FT                   /note="Contributes to redox potential value"
FT                   /evidence="ECO:0000250"
FT   SITE            122
FT                   /note="Lowers pKa of C-terminal Cys of first active site"
FT                   /evidence="ECO:0000250"
FT   SITE            400
FT                   /note="Contributes to redox potential value"
FT                   /evidence="ECO:0000250"
FT   SITE            401
FT                   /note="Contributes to redox potential value"
FT                   /evidence="ECO:0000250"
FT   SITE            463
FT                   /note="Lowers pKa of C-terminal Cys of second active site"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         202
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P09103"
FT   MOD_RES         224
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P09103"
FT   MOD_RES         273
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P09103"
FT   MOD_RES         333
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P07237"
FT   MOD_RES         359
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P07237"
FT   MOD_RES         429
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P07237"
FT   DISULFID        55..58
FT                   /note="Redox-active"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT   DISULFID        399..402
FT                   /note="Redox-active"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT   CONFLICT        39..40
FT                   /note="AL -> P (in Ref. 1; CAA26675)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   509 AA;  56951 MW;  3056107F5E8B1B54 CRC64;
     MLSRALLCLA LAWAARVGAD ALEEEDNVLV LKKSNFAEAL AAHNYLLVEF YAPWCGHCKA
     LAPEYAKAAA KLKAEGSEIR LAKVDATEES DLAQQYGVRG YPTIKFFKNG DTASPKEYTA
     GREADDIVNW LKKRTGPAAT TLSDTAAAES LVDSSEVTVI GFFKDAGSDS AKQFLLAAEA
     VDDIPFGITS NSDVFSKYQL DKDGVVLFKK FDEGRNNFEG EITKEKLLDF IKHNQLPLVI
     EFTEQTAPKI FGGEIKTHIL LFLPKSVSDY DGKLSNFKKA AEGFKGKILF IFIDSDHTDN
     QRILEFFGLK KEECPAVRLI TLEEEMTKYK PESDELTAEK ITQFCHHFLE GKIKPHLMSQ
     ELPEDWDKQP VKVLVGKNFE EVAFDEKKNV FVEFYAPWCG HCKQLAPIWD KLGETYKDHE
     NIVIAKMDST ANEVEAVKVH SFPTLKFFPA SADRTVIDYN GERTLDGFKK FLESGGQDGA
     GDNDDLDLEE ALEPDMEEDD DQKAVKDEL
//