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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
Protein disulfide-isomerase, also known as the beta-[[Protein subunit|subunit]] of [[prolyl 4-hydroxylase]] (P4HB), is an [[enzyme]] that in humans encoded by the ''P4HB'' [[gene]]. The human ''P4HB'' gene is localized in chromosome 17q25.<ref name="pmid8111381">{{cite journal | vauthors = Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT, Leoni PR, Bhattacharya S, Pease RJ, Cullen PM | title = Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein | journal = Human Molecular Genetics | volume = 2 | issue = 12 | pages = 2109–16 | date = December 1993 | pmid = 8111381 | pmc =  | doi = 10.1093/hmg/2.12.2109 }}</ref><ref name="entrez">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5034|title=Entrez Gene: P4HB procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide|accessdate=}}</ref><ref>{{cite journal | vauthors = Galligan JJ, Petersen DR | title = The human protein disulfide isomerase gene family | journal = Human Genomics | volume = 6 | pages =  6| date = July 2012 | pmid = 23245351 | pmc = 3500226 | doi = 10.1186/1479-7364-6-6 }}</ref><ref>{{cite journal | vauthors = Pajunen L, Jones TA, Goddard A, Sheer D, Solomon E, Pihlajaniemi T, Kivirikko KI | title = Regional assignment of the human gene coding for a multifunctional polypeptide (P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25 | journal = Cytogenetics and Cell Genetics | volume = 56 | issue = 3–4 | pages = 165–8 | date = 1991-01-01 | pmid = 1647289 | doi=10.1159/000133078}}</ref> Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an [[oxidoreductase]] for [[disulfide]] formation, breakage, and [[isomerization]].<ref>{{cite journal | vauthors = Lumb RA, Bulleid NJ | title = Is protein disulfide isomerase a redox-dependent molecular chaperone? | journal = The EMBO Journal | volume = 21 | issue = 24 | pages = 6763–70 | date = December 2002 | pmid = 12485997 | pmc = 139105 | doi=10.1093/emboj/cdf685}}</ref> The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.<ref>{{cite journal | vauthors = Bastos-Aristizabal S, Kozlov G, Gehring K | title = Structural insight into the dimerization of human protein disulfide isomerase | journal = Protein Science | volume = 23 | issue = 5 | pages = 618–26 | date = May 2014 | pmid = 24549644 | pmc = 4005713 | doi = 10.1002/pro.2444 }}</ref><ref>{{cite journal | vauthors = Winter J, Klappa P, Freedman RB, Lilie H, Rudolph R | title = Catalytic activity and chaperone function of human protein-disulfide isomerase are required for the efficient refolding of proinsulin | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 310–7 | date = January 2002 | pmid = 11694508 | doi = 10.1074/jbc.M107832200 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
P4HB has four [[Thioredoxin domain|thioredoxin]] domains (a, b, b’, and a’), with two CGHC [[active site]]s in the a and a’ domains. In both the reduced and oxidized state, these domains are arranged as a horseshoe shape. In reduced P4HB, domains a, b, and b' are in the same plane, while domain a' twists out at an ∼45° angle. When oxidized, the four domains stay in the same plane, and the distance between the active sites is larger than that in the reduced state. The oxidized form also exposes more [[Hydrophobic effect|hydrophobic]] areas and possesses a larger cleft to facilitate substrate binding.<ref>{{cite journal | vauthors = Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H | title = The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites | journal = Cell | volume = 124 | issue = 1 | pages = 61–73 | date = January 2006 | pmid = 16413482 | doi = 10.1016/j.cell.2005.10.044 }}</ref><ref>{{cite journal | vauthors = Wang C, Li W, Ren J, Fang J, Ke H, Gong W, Feng W, Wang CC | title = Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase | journal = Antioxidants & Redox Signaling | volume = 19 | issue = 1 | pages = 36–45 | date = July 2013 | pmid = 22657537 | doi = 10.1089/ars.2012.4630 }}</ref> P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB’s activity.<ref>{{cite journal | vauthors = Bastos-Aristizabal S, Kozlov G, Gehring K | title = Structural insight into the dimerization of human protein disulfide isomerase | language = en | journal = Protein Science | volume = 23 | issue = 5 | pages = 618–26 | date = May 2014 | pmid = 24549644 | pmc = 4005713 | doi = 10.1002/pro.2444 }}</ref>
| image = PBB_Protein_P4HB_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1bjx.
| PDB = {{PDB2|1bjx}}, {{PDB2|1mek}}, {{PDB2|1x5c}}, {{PDB2|2bjx}}
| Name = Procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide
| HGNCid = 8548
| Symbol = P4HB
| AltSymbols =; DSI; ERBA2L; GIT; PDI; PDIA1; PHDB; PO4DB; PO4HB; PROHB
| OMIM = 176790
| ECnumber = 
| Homologene = 55495
| MGIid = 97464
| GeneAtlas_image1 = PBB_GE_P4HB_200656_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_P4HB_200654_at_tn.png
| Function = {{GNF_GO|id=GO:0003756 |text = protein disulfide isomerase activity}} {{GNF_GO|id=GO:0004656 |text = procollagen-proline 4-dioxygenase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0009055 |text = electron carrier activity}} {{GNF_GO|id=GO:0015035 |text = protein disulfide oxidoreductase activity}} {{GNF_GO|id=GO:0016853 |text = isomerase activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0005792 |text = microsome}} {{GNF_GO|id=GO:0005793 |text = ER-Golgi intermediate compartment}} {{GNF_GO|id=GO:0009986 |text = cell surface}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006457 |text = protein folding}} {{GNF_GO|id=GO:0018401 |text = peptidyl-proline hydroxylation to 4-hydroxy-L-proline}} {{GNF_GO|id=GO:0045454 |text = cell redox homeostasis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5034
    | Hs_Ensembl = ENSG00000185624
    | Hs_RefseqProtein = NP_000909
    | Hs_RefseqmRNA = NM_000918
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 77394326
    | Hs_GenLoc_end = 77411680
    | Hs_Uniprot = P07237
    | Mm_EntrezGene = 18453
    | Mm_Ensembl = ENSMUSG00000025130
    | Mm_RefseqmRNA = NM_011032
    | Mm_RefseqProtein = NP_035162
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 120376394
    | Mm_GenLoc_end = 120389026
    | Mm_Uniprot = Q3TF72
  }}
}}
'''Procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide''', also known as '''P4HB''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: P4HB procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5034| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
| section_title =  
| summary_text = This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex.<ref name="entrez">{{cite web | title = Entrez Gene: P4HB procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5034| accessdate = }}</ref>
}}


==References==
This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits [[Protein aggregation|aggregation]] of misfolded proteins in a concentration-dependent manner, its ability to bind [[thyroid hormone]], its role in both the influx and efflux of [[S-Nitrosothiol|S-nitrosothiol]]-bound [[nitric oxide]], and its function as a subunit of the microsomal [[Triglyceride|triglyceride transfer protein]] complex.<ref name="entrez" />
{{reflist|2}}
 
==Further reading==
== Clinical significance ==
{{refbegin | 2}}
P4HB is a [[risk factor]] of [[Amyotrophic lateral sclerosis|amyotrophic lateral sclerosis (ALS)]]. Studies have shown significant genotypic associations for two SNPs in P4HB with FALS (familial ALS), rs876016 (P=0.0198) and rs2070872 (P=0.0046). Together with other [[Unfolded protein response|ER stress]] markers, P4HB is greatly elevated in ALS spinal cord.<ref>{{cite journal | vauthors = Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK | title = Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis | journal = Neurobiology of Disease | volume = 30 | issue = 3 | pages = 400–7 | date = June 2008 | pmid = 18440237 | doi = 10.1016/j.nbd.2008.02.009 }}</ref> P4HB can also be nitrosylated, and elevation of nitrosylated P4HB has been shown in [[Parkinson's disease|Parkinson's]] and [[Alzheimer's disease|Alzheimer's]] disease brain tissue, as well as in transgenic mutant [[Superoxide dismutase|superoxide dismutase 1]] mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues.<ref>{{cite journal | vauthors = Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD | title = Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis | journal = Brain | volume = 133 | issue = Pt 1 | pages = 105–16 | date = January 2010 | pmid = 19903735 | doi = 10.1093/brain/awp267 }}</ref><ref>{{cite journal | vauthors = Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA | title = S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration | language = en | journal = Nature | volume = 441 | issue = 7092 | pages = 513–7 | date = May 2006 | pmid = 16724068 | doi = 10.1038/nature04782 }}</ref> In addition to [[neurodegenerative diseases]], P4HB level is upregulated in [[glioblastoma multiforme]] (GBM) (brain tumor). Inhibition of P4HB attenuates resistance to [[temozolomide]], a standard GBM [[Chemotherapy|chemotherapeutic]] agent, via the PERK arm of endoplasmic reticulum stress response pathway.<ref>{{cite journal | vauthors = Sun S, Lee D, Ho AS, Pu JK, Zhang XQ, Lee NP, Day PJ, Lui WM, Fung CF, Leung GK | title = Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways | journal = Neuro-Oncology | volume = 15 | issue = 5 | pages = 562–77 | date = May 2013 | pmid = 23444257 | pmc = 3635523 | doi = 10.1093/neuonc/not005 }}</ref> Furthermore, [[heterozygous]] [[Missense mutation|missense]] mutation in P4HB can cause [[Cole carpenter syndrome|Cole-Carpenter syndrome]], a severe [[Osteogenesis imperfecta|bone fragility disorder]].<ref>{{cite journal | vauthors = Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, Bächinger HP, Moffatt P | title = Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB | journal = American Journal of Human Genetics | volume = 96 | issue = 3 | pages = 425–31 | date = March 2015 | pmid = 25683117 | pmc = 4375435 | doi = 10.1016/j.ajhg.2014.12.027 }}</ref>
{{PBB_Further_reading
 
| citations =
== Interactions ==
*{{cite journal  | author=Pihlajaniemi T, Myllylä R, Kivirikko KI |title=Prolyl 4-hydroxylase and its role in collagen synthesis. |journal=J. Hepatol. |volume=13 Suppl 3 |issue= |pages= S2-7 |year= 1992 |pmid= 1667665 |doi= }}
 
*{{cite journal  | author=Wilkinson B, Gilbert HF |title=Protein disulfide isomerase. |journal=Biochim. Biophys. Acta |volume=1699 |issue= 1-2 |pages= 35-44 |year= 2004 |pmid= 15158710 |doi= 10.1016/j.bbapap.2004.02.017 }}
P4HB has been shown to [[Protein-protein interaction|interact]] with [[UBQLN1]],<ref name=pmid12095988>{{cite journal | vauthors = Ko HS, Uehara T, Nomura Y | title = Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death | journal = The Journal of Biological Chemistry | volume = 277 | issue = 38 | pages = 35386–92 | date = September 2002 | pmid = 12095988 | doi = 10.1074/jbc.M203412200 }}</ref> [[ERO1LB]]<ref name=pmid11847130>{{cite journal | vauthors = Anelli T, Alessio M, Mezghrani A, Simmen T, Talamo F, Bachi A, Sitia R | title = ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family | journal = The EMBO Journal | volume = 21 | issue = 4 | pages = 835–44 | date = February 2002 | pmid = 11847130 | pmc = 125352 | doi = 10.1093/emboj/21.4.835 }}</ref><ref name=pmid11707400>{{cite journal | vauthors = Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R | title = Manipulation of oxidative protein folding and PDI redox state in mammalian cells | journal = The EMBO Journal | volume = 20 | issue = 22 | pages = 6288–96 | date = November 2001 | pmid = 11707400 | pmc = 125306 | doi = 10.1093/emboj/20.22.6288 }}</ref> and [[ERO1L]].<ref name=pmid11847130/><ref name=pmid11707400/>
*{{cite journal | author=Hochstrasser DF, Frutiger S, Paquet N, ''et al.'' |title=Human liver protein map: a reference database established by microsequencing and gel comparison. |journal=Electrophoresis |volume=13 |issue= 12 |pages= 992-1001 |year= 1993 |pmid= 1286669 |doi= }}
 
*{{cite journal | author=Chessler SD, Byers PH |title=Defective folding and stable association with protein disulfide isomerase/prolyl hydroxylase of type I procollagen with a deletion in the pro alpha 2(I) chain that preserves the Gly-X-Y repeat pattern. |journal=J. Biol. Chem. |volume=267 |issue= 11 |pages= 7751-7 |year= 1992 |pmid= 1339453 |doi= }}
== References ==
*{{cite journal | author=Vuori K, Myllylä R, Pihlajaniemi T, Kivirikko KI |title=Expression and site-directed mutagenesis of human protein disulfide isomerase in Escherichia coli. This multifunctional polypeptide has two independently acting catalytic sites for the isomerase activity. |journal=J. Biol. Chem. |volume=267 |issue= 11 |pages= 7211-4 |year= 1992 |pmid= 1559965 |doi= }}
{{reflist|33em}}
*{{cite journal | author=Tasanen K, Oikarinen J, Kivirikko KI, Pihlajaniemi T |title=Promoter of the gene for the multifunctional protein disulfide isomerase polypeptide. Functional significance of the six CCAAT boxes and other promoter elements. |journal=J. Biol. Chem. |volume=267 |issue= 16 |pages= 11513-9 |year= 1992 |pmid= 1597478 |doi= }}
 
*{{cite journal | author=Bauw G, Rasmussen HH, van den Bulcke M, ''et al.'' |title=Two-dimensional gel electrophoresis, protein electroblotting and microsequencing: a direct link between proteins and genes. |journal=Electrophoresis |volume=11 |issue= 7 |pages= 528-36 |year= 1990 |pmid= 1699755 |doi= 10.1002/elps.1150110703 }}
== Further reading ==
*{{cite journal | author=Ward LD, Hong J, Whitehead RH, Simpson RJ |title=Development of a database of amino acid sequences for human colon carcinoma proteins separated by two-dimensional polyacrylamide gel electrophoresis. |journal=Electrophoresis |volume=11 |issue= 10 |pages= 883-91 |year= 1991 |pmid= 2079031 |doi= 10.1002/elps.1150111019 }}
{{refbegin|33em}}
*{{cite journal | author=Tasanen K, Parkkonen T, Chow LT, ''et al.'' |title=Characterization of the human gene for a polypeptide that acts both as the beta subunit of prolyl 4-hydroxylase and as protein disulfide isomerase. |journal=J. Biol. Chem. |volume=263 |issue= 31 |pages= 16218-24 |year= 1988 |pmid= 2846539 |doi= }}
* {{cite journal | vauthors = Galligan JJ, Petersen DR | title = The human protein disulfide isomerase gene family | journal = Human Genomics | volume = 6 | pages = 6| date = July 2012 | pmid = 23245351 | pmc = 3500226 | doi = 10.1186/1479-7364-6-6 }}
*{{cite journal  | author=Koivu J, Myllylä R, Helaakoski T, ''et al.'' |title=A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. |journal=J. Biol. Chem. |volume=262 |issue= 14 |pages= 6447-9 |year= 1987 |pmid= 3032969 |doi= }}
* {{cite journal | vauthors = Wilkinson B, Gilbert HF | title = Protein disulfide isomerase | journal = Biochimica et Biophysica Acta | volume = 1699 | issue = 1–2 | pages = 35–44 | date = June 2004 | pmid = 15158710 | doi = 10.1016/j.bbapap.2004.02.017 }}
*{{cite journal | author=Pihlajaniemi T, Helaakoski T, Tasanen K, ''et al.'' |title=Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene. |journal=EMBO J. |volume=6 |issue= 3 |pages= 643-9 |year= 1987 |pmid= 3034602 |doi= }}
* {{cite journal | vauthors = Pihlajaniemi T, Myllylä R, Kivirikko KI | title = Prolyl 4-hydroxylase and its role in collagen synthesis | journal = Journal of Hepatology | volume = 13 Suppl 3 | issue = | pages = S2-7 | year = 1992 | pmid = 1667665 | doi = 10.1016/0168-8278(91)90002-S }}
*{{cite journal | author=Morris JI, Varandani PT |title=Characterization of a cDNA for human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase). |journal=Biochim. Biophys. Acta |volume=949 |issue= 2 |pages= 169-80 |year= 1988 |pmid= 3342239 |doi= }}
* {{cite journal | vauthors = Wilkinson B, Gilbert HF | title = Protein disulfide isomerase | journal = Biochimica et Biophysica Acta | volume = 1699 | issue = 1–2 | pages = 35–44 | date = June 2004 | pmid = 15158710 | doi = 10.1016/j.bbapap.2004.02.017 }}
*{{cite journal | author=Gosden JR, Middleton PG, Rout D, De Angelis C |title=Chromosomal localization of the human oncogene ERBA2. |journal=Cytogenet. Cell Genet. |volume=43 |issue= 3-4 |pages= 150-3 |year= 1987 |pmid= 3467900 |doi= }}
* {{cite journal | vauthors = Hochstrasser DF, Frutiger S, Paquet N, Bairoch A, Ravier F, Pasquali C, Sanchez JC, Tissot JD, Bjellqvist B, Vargas R | title = Human liver protein map: a reference database established by microsequencing and gel comparison | journal = Electrophoresis | volume = 13 | issue = 12 | pages = 992–1001 | date = December 1992 | pmid = 1286669 | doi = 10.1002/elps.11501301201 }}
*{{cite journal | author=Cheng SY, Gong QH, Parkison C, ''et al.'' |title=The nucleotide sequence of a human cellular thyroid hormone binding protein present in endoplasmic reticulum. |journal=J. Biol. Chem. |volume=262 |issue= 23 |pages= 11221-7 |year= 1987 |pmid= 3611107 |doi= }}
* {{cite journal | vauthors = Chessler SD, Byers PH | title = Defective folding and stable association with protein disulfide isomerase/prolyl hydroxylase of type I procollagen with a deletion in the pro alpha 2(I) chain that preserves the Gly-X-Y repeat pattern | journal = The Journal of Biological Chemistry | volume = 267 | issue = 11 | pages = 7751–7 | date = April 1992 | pmid = 1339453 | doi =  }}
*{{cite journal | author=Helaakoski T, Annunen P, Vuori K, ''et al.'' |title=Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2 tetramer with the protein disulfide-isomerase/beta subunit. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 10 |pages= 4427-31 |year= 1995 |pmid= 7753822 |doi=  }}
* {{cite journal | vauthors = Vuori K, Myllylä R, Pihlajaniemi T, Kivirikko KI | title = Expression and site-directed mutagenesis of human protein disulfide isomerase in Escherichia coli. This multifunctional polypeptide has two independently acting catalytic sites for the isomerase activity | journal = The Journal of Biological Chemistry | volume = 267 | issue = 11 | pages = 7211–4 | date = April 1992 | pmid = 1559965 | doi =  }}
*{{cite journal | author=Shoulders CC, Brett DJ, Bayliss JD, ''et al.'' |title=Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. |journal=Hum. Mol. Genet. |volume=2 |issue= 12 |pages= 2109-16 |year= 1994 |pmid= 8111381 |doi=  }}
* {{cite journal | vauthors = Tasanen K, Oikarinen J, Kivirikko KI, Pihlajaniemi T | title = Promoter of the gene for the multifunctional protein disulfide isomerase polypeptide. Functional significance of the six CCAAT boxes and other promoter elements | journal = The Journal of Biological Chemistry | volume = 267 | issue = 16 | pages = 11513–9 | date = June 1992 | pmid = 1597478 | doi =  }}
*{{cite journal | author=Kemmink J, Darby NJ, Dijkstra K, ''et al.'' |title=Nuclear magnetic resonance characterization of the N-terminal thioredoxin-like domain of protein disulfide isomerase. |journal=Protein Sci. |volume=4 |issue= 12 |pages= 2587-93 |year= 1996 |pmid= 8580850 |doi=  }}
* {{cite journal | vauthors = Bauw G, Rasmussen HH, van den Bulcke M, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J | title = Two-dimensional gel electrophoresis, protein electroblotting and microsequencing: a direct link between proteins and genes | journal = Electrophoresis | volume = 11 | issue = 7 | pages = 528–36 | date = July 1990 | pmid = 1699755 | doi = 10.1002/elps.1150110703 }}
*{{cite journal | author=Kemmink J, Darby NJ, Dijkstra K, ''et al.'' |title=Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy. |journal=Biochemistry |volume=35 |issue= 24 |pages= 7684-91 |year= 1996 |pmid= 8672469 |doi= 10.1021/bi960335m }}
* {{cite journal | vauthors = Ward LD, Hong J, Whitehead RH, Simpson RJ | title = Development of a database of amino acid sequences for human colon carcinoma proteins separated by two-dimensional polyacrylamide gel electrophoresis | journal = Electrophoresis | volume = 11 | issue = 10 | pages = 883–91 | date = October 1990 | pmid = 2079031 | doi = 10.1002/elps.1150111019 }}
*{{cite journal  | author=Ji H, Reid GE, Moritz RL, ''et al.'' |title=A two-dimensional gel database of human colon carcinoma proteins. |journal=Electrophoresis |volume=18 |issue= 3-4 |pages= 605-13 |year= 1997 |pmid= 9150948 |doi= 10.1002/elps.1150180344 }}
* {{cite journal | vauthors = Tasanen K, Parkkonen T, Chow LT, Kivirikko KI, Pihlajaniemi T | title = Characterization of the human gene for a polypeptide that acts both as the beta subunit of prolyl 4-hydroxylase and as protein disulfide isomerase | journal = The Journal of Biological Chemistry | volume = 263 | issue = 31 | pages = 16218–24 | date = November 1988 | pmid = 2846539 | doi =  }}
}}
* {{cite journal | vauthors = Koivu J, Myllylä R, Helaakoski T, Pihlajaniemi T, Tasanen K, Kivirikko KI | title = A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase | journal = The Journal of Biological Chemistry | volume = 262 | issue = 14 | pages = 6447–9 | date = May 1987 | pmid = 3032969 | doi =  }}
* {{cite journal | vauthors = Pihlajaniemi T, Helaakoski T, Tasanen K, Myllylä R, Huhtala ML, Koivu J, Kivirikko KI | title = Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene | journal = The EMBO Journal | volume = 6 | issue = 3 | pages = 643–9 | date = March 1987 | pmid = 3034602 | pmc = 553446 | doi =  }}
* {{cite journal | vauthors = Morris JI, Varandani PT | title = Characterization of a cDNA for human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase) | journal = Biochimica et Biophysica Acta | volume = 949 | issue = 2 | pages = 169–80 | date = February 1988 | pmid = 3342239 | doi = 10.1016/0167-4781(88)90080-2 }}
* {{cite journal | vauthors = Gosden JR, Middleton PG, Rout D, De Angelis C | title = Chromosomal localization of the human oncogene ERBA2 | journal = Cytogenetics and Cell Genetics | volume = 43 | issue = 3–4 | pages = 150–3 | year = 1987 | pmid = 3467900 | doi = 10.1159/000132313 }}
* {{cite journal | vauthors = Cheng SY, Gong QH, Parkison C, Robinson EA, Appella E, Merlino GT, Pastan I | title = The nucleotide sequence of a human cellular thyroid hormone binding protein present in endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 262 | issue = 23 | pages = 11221–7 | date = August 1987 | pmid = 3611107 | doi =  }}
* {{cite journal | vauthors = Helaakoski T, Annunen P, Vuori K, MacNeil IA, Pihlajaniemi T, Kivirikko KI | title = Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2 tetramer with the protein disulfide-isomerase/beta subunit | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 10 | pages = 4427–31 | date = May 1995 | pmid = 7753822 | pmc = 41957 | doi = 10.1073/pnas.92.10.4427 }}
* {{cite journal | vauthors = Kemmink J, Darby NJ, Dijkstra K, Scheek RM, Creighton TE | title = Nuclear magnetic resonance characterization of the N-terminal thioredoxin-like domain of protein disulfide isomerase | journal = Protein Science | volume = 4 | issue = 12 | pages = 2587–93 | date = December 1995 | pmid = 8580850 | pmc = 2143042 | doi = 10.1002/pro.5560041216 }}
* {{cite journal | vauthors = Kemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE | title = Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy | journal = Biochemistry | volume = 35 | issue = 24 | pages = 7684–91 | date = June 1996 | pmid = 8672469 | doi = 10.1021/bi960335m }}
* {{cite journal | vauthors = Ji H, Reid GE, Moritz RL, Eddes JS, Burgess AW, Simpson RJ | title = A two-dimensional gel database of human colon carcinoma proteins | journal = Electrophoresis | volume = 18 | issue = 3–4 | pages = 605–13 | year = 1997 | pmid = 9150948 | doi = 10.1002/elps.1150180344 }}
{{refend}}
{{refend}}


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Latest revision as of 17:27, 7 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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View/Edit Human

Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25.[1][2][3][4] Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization.[5] The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.[6][7]

Structure

P4HB has four thioredoxin domains (a, b, b’, and a’), with two CGHC active sites in the a and a’ domains. In both the reduced and oxidized state, these domains are arranged as a horseshoe shape. In reduced P4HB, domains a, b, and b' are in the same plane, while domain a' twists out at an ∼45° angle. When oxidized, the four domains stay in the same plane, and the distance between the active sites is larger than that in the reduced state. The oxidized form also exposes more hydrophobic areas and possesses a larger cleft to facilitate substrate binding.[8][9] P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB’s activity.[10]

Function

This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex.[2]

Clinical significance

P4HB is a risk factor of amyotrophic lateral sclerosis (ALS). Studies have shown significant genotypic associations for two SNPs in P4HB with FALS (familial ALS), rs876016 (P=0.0198) and rs2070872 (P=0.0046). Together with other ER stress markers, P4HB is greatly elevated in ALS spinal cord.[11] P4HB can also be nitrosylated, and elevation of nitrosylated P4HB has been shown in Parkinson's and Alzheimer's disease brain tissue, as well as in transgenic mutant superoxide dismutase 1 mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues.[12][13] In addition to neurodegenerative diseases, P4HB level is upregulated in glioblastoma multiforme (GBM) (brain tumor). Inhibition of P4HB attenuates resistance to temozolomide, a standard GBM chemotherapeutic agent, via the PERK arm of endoplasmic reticulum stress response pathway.[14] Furthermore, heterozygous missense mutation in P4HB can cause Cole-Carpenter syndrome, a severe bone fragility disorder.[15]

Interactions

P4HB has been shown to interact with UBQLN1,[16] ERO1LB[17][18] and ERO1L.[17][18]

References

  1. ↑ Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT, Leoni PR, Bhattacharya S, Pease RJ, Cullen PM (December 1993). "Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein". Human Molecular Genetics. 2 (12): 2109–16. doi:10.1093/hmg/2.12.2109. PMID 8111381.
  2. ↑ 2.0 2.1 "Entrez Gene: P4HB procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide".
  3. ↑ Galligan JJ, Petersen DR (July 2012). "The human protein disulfide isomerase gene family". Human Genomics. 6: 6. doi:10.1186/1479-7364-6-6. PMC 3500226. PMID 23245351.
  4. ↑ Pajunen L, Jones TA, Goddard A, Sheer D, Solomon E, Pihlajaniemi T, Kivirikko KI (1991-01-01). "Regional assignment of the human gene coding for a multifunctional polypeptide (P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25". Cytogenetics and Cell Genetics. 56 (3–4): 165–8. doi:10.1159/000133078. PMID 1647289.
  5. ↑ Lumb RA, Bulleid NJ (December 2002). "Is protein disulfide isomerase a redox-dependent molecular chaperone?". The EMBO Journal. 21 (24): 6763–70. doi:10.1093/emboj/cdf685. PMC 139105. PMID 12485997.
  6. ↑ Bastos-Aristizabal S, Kozlov G, Gehring K (May 2014). "Structural insight into the dimerization of human protein disulfide isomerase". Protein Science. 23 (5): 618–26. doi:10.1002/pro.2444. PMC 4005713. PMID 24549644.
  7. ↑ Winter J, Klappa P, Freedman RB, Lilie H, Rudolph R (January 2002). "Catalytic activity and chaperone function of human protein-disulfide isomerase are required for the efficient refolding of proinsulin". The Journal of Biological Chemistry. 277 (1): 310–7. doi:10.1074/jbc.M107832200. PMID 11694508.
  8. ↑ Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H (January 2006). "The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites". Cell. 124 (1): 61–73. doi:10.1016/j.cell.2005.10.044. PMID 16413482.
  9. ↑ Wang C, Li W, Ren J, Fang J, Ke H, Gong W, Feng W, Wang CC (July 2013). "Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase". Antioxidants & Redox Signaling. 19 (1): 36–45. doi:10.1089/ars.2012.4630. PMID 22657537.
  10. ↑ Bastos-Aristizabal S, Kozlov G, Gehring K (May 2014). "Structural insight into the dimerization of human protein disulfide isomerase". Protein Science. 23 (5): 618–26. doi:10.1002/pro.2444. PMC 4005713. PMID 24549644.
  11. ↑ Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK (June 2008). "Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis". Neurobiology of Disease. 30 (3): 400–7. doi:10.1016/j.nbd.2008.02.009. PMID 18440237.
  12. ↑ Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD (January 2010). "Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis". Brain. 133 (Pt 1): 105–16. doi:10.1093/brain/awp267. PMID 19903735.
  13. ↑ Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (May 2006). "S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration". Nature. 441 (7092): 513–7. doi:10.1038/nature04782. PMID 16724068.
  14. ↑ Sun S, Lee D, Ho AS, Pu JK, Zhang XQ, Lee NP, Day PJ, Lui WM, Fung CF, Leung GK (May 2013). "Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways". Neuro-Oncology. 15 (5): 562–77. doi:10.1093/neuonc/not005. PMC 3635523. PMID 23444257.
  15. ↑ Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, Bächinger HP, Moffatt P (March 2015). "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB". American Journal of Human Genetics. 96 (3): 425–31. doi:10.1016/j.ajhg.2014.12.027. PMC 4375435. PMID 25683117.
  16. ↑ Ko HS, Uehara T, Nomura Y (September 2002). "Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death". The Journal of Biological Chemistry. 277 (38): 35386–92. doi:10.1074/jbc.M203412200. PMID 12095988.
  17. ↑ 17.0 17.1 Anelli T, Alessio M, Mezghrani A, Simmen T, Talamo F, Bachi A, Sitia R (February 2002). "ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family". The EMBO Journal. 21 (4): 835–44. doi:10.1093/emboj/21.4.835. PMC 125352. PMID 11847130.
  18. ↑ 18.0 18.1 Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R (November 2001). "Manipulation of oxidative protein folding and PDI redox state in mammalian cells". The EMBO Journal. 20 (22): 6288–96. doi:10.1093/emboj/20.22.6288. PMC 125306. PMID 11707400.

Further reading

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