Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HBgene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.
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. P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB’s activity.
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.
^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. PMID8111381.
^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. PMID1647289.
^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. PMID11694508.
^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. PMID16413482.
^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. PMID22657537.
^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. PMID18440237.
^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. PMID19903735.
^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. PMID16724068.
^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. PMID12095988.
Hochstrasser DF, Frutiger S, Paquet N, Bairoch A, Ravier F, Pasquali C, Sanchez JC, Tissot JD, Bjellqvist B, Vargas R (December 1992). "Human liver protein map: a reference database established by microsequencing and gel comparison". Electrophoresis. 13 (12): 992–1001. doi:10.1002/elps.11501301201. PMID1286669.
Chessler SD, Byers PH (April 1992). "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". The Journal of Biological Chemistry. 267 (11): 7751–7. PMID1339453.
Vuori K, Myllylä R, Pihlajaniemi T, Kivirikko KI (April 1992). "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". The Journal of Biological Chemistry. 267 (11): 7211–4. PMID1559965.
Tasanen K, Oikarinen J, Kivirikko KI, Pihlajaniemi T (June 1992). "Promoter of the gene for the multifunctional protein disulfide isomerase polypeptide. Functional significance of the six CCAAT boxes and other promoter elements". The Journal of Biological Chemistry. 267 (16): 11513–9. PMID1597478.
Bauw G, Rasmussen HH, van den Bulcke M, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (July 1990). "Two-dimensional gel electrophoresis, protein electroblotting and microsequencing: a direct link between proteins and genes". Electrophoresis. 11 (7): 528–36. doi:10.1002/elps.1150110703. PMID1699755.
Ward LD, Hong J, Whitehead RH, Simpson RJ (October 1990). "Development of a database of amino acid sequences for human colon carcinoma proteins separated by two-dimensional polyacrylamide gel electrophoresis". Electrophoresis. 11 (10): 883–91. doi:10.1002/elps.1150111019. PMID2079031.
Tasanen K, Parkkonen T, Chow LT, Kivirikko KI, Pihlajaniemi T (November 1988). "Characterization of the human gene for a polypeptide that acts both as the beta subunit of prolyl 4-hydroxylase and as protein disulfide isomerase". The Journal of Biological Chemistry. 263 (31): 16218–24. PMID2846539.
Koivu J, Myllylä R, Helaakoski T, Pihlajaniemi T, Tasanen K, Kivirikko KI (May 1987). "A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase". The Journal of Biological Chemistry. 262 (14): 6447–9. PMID3032969.
Morris JI, Varandani PT (February 1988). "Characterization of a cDNA for human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase)". Biochimica et Biophysica Acta. 949 (2): 169–80. doi:10.1016/0167-4781(88)90080-2. PMID3342239.
Gosden JR, Middleton PG, Rout D, De Angelis C (1987). "Chromosomal localization of the human oncogene ERBA2". Cytogenetics and Cell Genetics. 43 (3–4): 150–3. doi:10.1159/000132313. PMID3467900.
Cheng SY, Gong QH, Parkison C, Robinson EA, Appella E, Merlino GT, Pastan I (August 1987). "The nucleotide sequence of a human cellular thyroid hormone binding protein present in endoplasmic reticulum". The Journal of Biological Chemistry. 262 (23): 11221–7. PMID3611107.
Kemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE (June 1996). "Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy". Biochemistry. 35 (24): 7684–91. doi:10.1021/bi960335m. PMID8672469.
Ji H, Reid GE, Moritz RL, Eddes JS, Burgess AW, Simpson RJ (1997). "A two-dimensional gel database of human colon carcinoma proteins". Electrophoresis. 18 (3–4): 605–13. doi:10.1002/elps.1150180344. PMID9150948.