P4HB

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Protein-coding gene in the species Homo sapiens

title: "P4HB" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["endoplasmic-reticulum-resident-proteins"] description: "Protein-coding gene in the species Homo sapiens" topic_path: "general/endoplasmic-reticulum-resident-proteins" source: "https://en.wikipedia.org/wiki/P4HB" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

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. 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.

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 a ~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.

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.

Clinical significance

P4HB can 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. 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. Furthermore, heterozygous missense mutation in P4HB can cause Cole-Carpenter syndrome, a severe bone fragility disorder.

Interactions

P4HB has been shown to interact with UBQLN1, ERO1LB and ERO1L.

References

(December 1993). "Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein". Human Molecular Genetics.
"Entrez Gene: P4HB procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide".
(July 2012). "The human protein disulfide isomerase gene family". Human Genomics.
(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.
(December 2002). "Is protein disulfide isomerase a redox-dependent molecular chaperone?". The EMBO Journal.
(May 2014). "Structural insight into the dimerization of human protein disulfide isomerase". Protein Science.
(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.
(January 2006). "The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites". Cell.
(July 2013). "Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase". Antioxidants & Redox Signaling.
(May 2014). "Structural insight into the dimerization of human protein disulfide isomerase". Protein Science.
(January 2010). "Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis". Brain.
(May 2006). "S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration". Nature.
(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.
(March 2015). "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB". American Journal of Human Genetics.
(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.
(February 2002). "ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family". The EMBO Journal.
(November 2001). "Manipulation of oxidative protein folding and PDI redox state in mammalian cells". The EMBO Journal.

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