Disease relevance of P4HB

• Using a serum from a patient with an autoimmune disease, we have recently described a novel 55 000-dalton antigen (p55) in the nucleus of several animal cells including human ones [1].
• We report here on the expression of human PDI in Escherichia coli with three different signal sequences [2].
• The determination of the atomic structure of the MTP-PDI heterodimer has important implications for the treatment of those forms of hyperlipidaemia associated with the overproduction of very-low-density lipoproteins, which predispose to premature coronary heart disease [3].
• Precursor lesions in the GIT include flat dysplasias, adenomas, dysplasia superimposed on nonneoplastic polyps, endocrine cell dysplasia, ACF, and condyloma accuminatum [4].
• We have established that the episulfonium ion of CEG can adduct PDI and may have important toxicologic significance for 1,2-dichloroethane toxicity [5].

Psychiatry related information on P4HB

• Aluminium increases permeability of the blood-brain barrier to labelled DSIP and beta-endorphin: possible implications for senile and dialysis dementia [6].
• Finally, recent results suggest pathogenic roles for GIT proteins in Huntington's disease and HIV infection [7].
• DSIP-LI levels were substantially lower in rapid eye movement sleep (P < 0.005) and somewhat lower in SWS (P < 0.05) compared to awake values [8].
• Since delta-sleep-inducing peptide (DSIP) was isolated in 1977, numerous reports have suggested that this nonapeptide stimulates delta-sleep [slow wave sleep (SWS)] [8].
• Although DSIP-like immunoreactivity (DSIP-LI) has been found in the serum of many animals and man, its diurnal rhythm and relation to sleep stages have not been well defined [8].

High impact information on P4HB

• Furthermore, we demonstrate that human cytomegalovirus US3 protein inhibits CD8(+) T cell recognition by mediating PDI degradation, verifying the functional relevance of PDI-catalyzed peptide editing in controlling intracellular pathogens [9].
• Previously, we showed PAK-PIX-GIT targets and regulates focal adhesions; here, we uncover a different function for the complex at the centrosome [10].
• The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A [10].
• In the endoplasmic reticulum of eukaryotes, disulfide formation is catalyzed by protein disulfide isomerase (PDI); by contrast, prokaryotes produce a family of disulfide bond (Dsb) proteins, which together achieve an equivalent outcome in the bacterial periplasm [11].
• We found that protein disulfide isomerase (PDI) facilitates CT retrotranslocation, whereas ERp72, a PDI-like protein, mediates its ER retention [12].

Chemical compound and disease context of P4HB

• Before octreotide therapy, 2 patients had normal responses of plasma glucose and insulin to 75-g OGTT (normal glucose tolerance: NGT) and 4 showed hyperinsulinemia or glucose intolerance (glucose intolerance: GIT) [13].
• In conclusion, using a global proteomics approach, PDI was identified to play an important role in glioma cell invasion, and its action was effectively inhibited by bacitracin [14].
• Provocation with pentagastrin in patients with midgut carcinoid syndrome resulted in increased peripheral levels of 5HT, but not of DSIP [15].
• By immunocytochemistry, delta sleep-inducing peptide (DSIP) was demonstrated to coexist with serotonin (5-HT) in a majority of midgut carcinoid tumour cells studied in biopsies and long-term cell cultures [15].
• We examined, first, the influence of DSIP on ACTH and cortisol release following stimulation with human corticotropin-releasing hormone (h-CRH; 1.0 microgram/kg body weight, and 0.5 microgram/kg body weight, respectively) in healthy young men (n = 5 in each condition) [16].

Biological context of P4HB

• Manipulation of oxidative protein folding and PDI redox state in mammalian cells [17].
• The nucleotide sequence of a human cellular thyroid hormone binding protein present in endoplasmic reticulum [18].
• The ERp60 gene was mapped by fluorescence in situ hybridization to 15q15 and the processed gene to 1q21, so that neither was located on the same chromosome as the human PDI and thioredoxin genes [19].
• Herein we show that ovine aortic valvular endothelial cells and circulating endothelial progenitor cells (EPCs) seeded onto PGA/P4HB proliferate in response to vascular endothelial growth factor and transdifferentiate to a mesenchymal phenotype in response to transforming growth factor beta(1) [20].
• These results demonstrate that PGA/P4HB provides a conducive environment for cellular proliferation, differentiation, and tissue development [20].

Anatomical context of P4HB

• Meanwhile, p55 was absent from the residual nuclear matrices (achromatinic nuclei) [1].
• We have now found that p55 is associated with chromatin structures as it is released from the nucleus of mink cell fibroblasts by saline + DNase treatments [1].
• We investigated the secretion and cell surface expression of PDI and other chaperones in the FRTL5 thyroid cell line, and then studied the characteristics of the interaction between TG and PDI [21].
• It has been established that PDI is continuously secreted from cells that are net producers of NO-like endothelial cells [22].
• The notion that PDI acts as an "escort" for immature TG in acidic post-endoplasmic reticulum compartments is discussed [21].

Associations of P4HB with chemical compounds

• Analysis by sucrose gradient centrifugation of the nuclear material released in these conditions indicated that p55 co-migrated with core histones [1].
• Evidence has also been obtained showing that in a NO- and O2-rich environment, PDI can form N2O3 in its hydrophobic domains [22].
• S-nitrosoglutathione (GSNO) denitrosation activity of recombinant human protein disulfide isomerase (PDI) has been kinetically characterized by monitoring the loss of the S-NO absorbance, using a NO electrode, and with the aid of the fluorogenic NOx probe 2,3-diaminonaphthalene [22].
• Furthermore, measurements of intrinsic fluorescence and difference absorbance during denaturation show that abb'a' is much more labile to heat or guanidine hydrochloride denaturation than wild-type PDI [23].
• In vitro, the combined action of ROS and PDI, in the presence of free glutathione (reduced/oxidized), increased the solubility of this misassembled Tg and partially restored the ability of Tg to synthesize hormones [24].

Physical interactions of P4HB

• We observed on living cells or membrane preparations that PDI specifically binds TG in acidic conditions, and that only BD is involved in binding [21].
• When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity [25].
• The K(D) value of PDI binding to ERp57 was calculated as 5.46x10(-6)M with the BIACORE system [26].
• Both PDI and the collagen-binding protein hsp47 showed a similar pH-dependent interaction with folded collagen, dissociating when the pH was lowered to pH 6 [27].

Enzymatic interactions of P4HB

• Here we show that both human Ero1-Lalpha and Ero1-Lbeta (hEROs) facilitate disulfide bond formation in immunoglobulin subunits by selectively oxidizing PDI [17].
• Based on these results, it is proposed that PDI catalyzes the oligomerization of Tg through the disulfide linkage and its deoligomerization in the molecular fate, and this process may require a specific molecular form of Tg, optimally unfolded/reduced, in a proper redox state [28].

Regulatory relationships of P4HB

• Interestingly, low concentrations of ERp57 enhanced the chaperone activity of PDI, while high concentrations interfered with chaperone activity [26].

Other interactions of P4HB

• We report here that all the PDI domain constructs and PDI/ERp57 hybrid polypeptides tested were more effectively associated with the alpha(II) subunit than the alpha(I) subunit [29].
• Here, we investigated the role of two molecular chaperones, protein disulfide isomerase (PDI) and immunoglobulin heavy chain-binding protein (BiP), present in the follicular lumen, on the multimerization process due to oxidation using both native Tg and its N-terminal domain (NTD) [30].
• We demonstrated that PDI, but also other chaperones such as calnexin and KDEL-containing proteins are exposed at the cell surface [21].
• Protein disulfide isomerase (PDI) functions as an isomerase to catalyze thiol:disulfide exchange, as a chaperone to assist protein folding, and as a subunit of prolyl-4-hydroxylase and microsomal triglyceride transfer protein [31].
• A low-resolution NMR structure of the b domain revealed that this domain adopts a fold similar to the PDI a domain and thioredoxin [Kemmink, J., Darby, N.J., Dijkstra, K., Nilges, M. and Creighton, T.E. (1997) Curr. Biol. 7, 239-245] [32].

Analytical, diagnostic and therapeutic context of P4HB

• Localization of p55 in synchronized cells was performed by indirect immunofluorescence and immunoprecipitation [1].
• Oligonucleotide-directed mutagenesis was used to convert either one or both of the -Cys-Gly-His-Cys- sequences to -Ser-Gly-His-Cys-. The PDI activity of both polypeptides containing a single modified sequence was about 50% of that of the wild-type polypeptide, whereas the polypeptide with two modified sequences had no isomerase activity [2].
• Scanning electron microscopy revealed signs of heterogeneous P4HB coating and fiber disruption, suggesting possible explanations for the observed mechanical properties [33].
• Many materials have been investigated in blood vessel tissue engineering, such as PGA, PLGA, P4HB [34].
• Dissection of the degradation process revealed that upon release from calnexin, extensively oxidized BACE457 transiently entered in disulfide-bonded complexes associated with the lumenal chaperones BiP and protein disulfide isomerase (PDI) before unfolding and dislocation into the cytosol for degradation [35].

References