P4HB

P4HB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1X5C, 1BJX, 2K18, 4JU5, 4EL1, 3BJ5, 1MEK, 2BJX, 3UEM, 4EKZ
Identifiers
Aliases	P4HB, DSI, ERBA2L, GIT, P4Hbeta, PDI, PDIA1, PHDB, PO4DB, PO4HB, PROHB, CLCRP1, prolyl 4-hydroxylase subunit beta
External IDs	OMIM: 176790; MGI: 97464; HomoloGene: 55495; GeneCards: P4HB; OMA:P4HB - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q25.3 Start 81,843,159 bp[1] End 81,860,856 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 E2|11 84.27 cM Start 120,451,124 bp[2] End 120,464,079 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium parotid gland body of pancreas jejunal mucosa mucosa of ileum islet of Langerhans right lobe of liver duodenum anterior pituitary beta cell Top expressed in lacrimal gland gastrula crypt of lieberkuhn of small intestine molar parotid gland Paneth cell calvaria renal corpuscle submandibular gland pyloric antrum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function isomerase activity integrin binding protein binding procollagen-proline 4-dioxygenase activity protein heterodimerization activity enzyme binding RNA binding protein disulfide isomerase activity Cellular component procollagen-proline 4-dioxygenase complex endoplasmic reticulum lumen membrane focal adhesion melanosome plasma membrane endoplasmic reticulum chaperone complex extracellular region endoplasmic reticulum extracellular exosome external side of plasma membrane endoplasmic reticulum-Golgi intermediate compartment extracellular matrix Biological process positive regulation of viral entry into host cell peptidyl-proline hydroxylation to 4-hydroxy-L-proline regulation of oxidative stress-induced intrinsic apoptotic signaling pathway cell redox homeostasis response to endoplasmic reticulum stress cellular response to hypoxia protein folding chylomicron assembly very-low-density lipoprotein particle assembly cellular response to oxidative stress post-translational protein modification interleukin-12-mediated signaling pathway interleukin-23-mediated signaling pathway cellular response to interleukin-7 Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5034 18453 Ensembl ENSG00000185624 ENSMUSG00000025130 UniProt P07237 P09103 RefSeq (mRNA) NM_000918 NM_011032 RefSeq (protein) NP_000909 NP_035162 Location (UCSC) Chr 17: 81.84 – 81.86 Mb Chr 11: 120.45 – 120.46 Mb PubMed search [3] [4]
Wikidata
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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.^[5][6][7][8] Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization.^[9] The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.^[10][11]

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.^[12][13] P4HB has been shown to dimerize in vivo via noncatalytic bb' domains. Formation of dimer blocks substrate-binding site and inhibits P4HB's activity.^[14]

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.^[6]

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.^[15][16] 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.^[17] Furthermore, heterozygous missense mutation in P4HB can cause Cole-Carpenter syndrome, a severe bone fragility disorder.^[18]

P4HB has been shown to interact with UBQLN1,^[19] ERO1LB^[20][21] and ERO1L.^[20][21]