P07237 · PDIA1_HUMAN
- ProteinProtein disulfide-isomerase
- GeneP4HB
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids508 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations and following phosphorylation by FAM20C, functions as a chaperone that inhibits aggregation of misfolded proteins (PubMed:32149426).
At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts as a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307).
At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts as a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307).
Miscellaneous
Reduces and may activate fusogenic properties of HIV-1 gp120 surface protein, thereby enabling HIV-1 entry into the cell.
Catalytic activity
Features
Showing features for active site, site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 53 | Nucleophile | ||||
Sequence: C | ||||||
Site | 54 | Contributes to redox potential value | ||||
Sequence: G | ||||||
Site | 55 | Contributes to redox potential value | ||||
Sequence: H | ||||||
Active site | 56 | Nucleophile | ||||
Sequence: C | ||||||
Site | 120 | Lowers pKa of C-terminal Cys of first active site | ||||
Sequence: R | ||||||
Active site | 397 | Nucleophile | ||||
Sequence: C | ||||||
Site | 398 | Contributes to redox potential value | ||||
Sequence: G | ||||||
Site | 399 | Contributes to redox potential value | ||||
Sequence: H | ||||||
Active site | 400 | Nucleophile | ||||
Sequence: C | ||||||
Site | 461 | Lowers pKa of C-terminal Cys of second active site | ||||
Sequence: R |
GO annotations
Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameProtein disulfide-isomerase
- EC number
- Short namesPDI
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP07237
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Peripheral membrane protein
Note: Highly abundant. In some cell types, seems to be also secreted or associated with the plasma membrane, where it undergoes constant shedding and replacement from intracellular sources (Probable). Localizes near CD4-enriched regions on lymphoid cell surfaces (PubMed:11181151).
Identified by mass spectrometry in melanosome fractions from stage I to stage IV (PubMed:10636893).
Colocalizes with MTTP in the endoplasmic reticulum (PubMed:23475612).
Identified by mass spectrometry in melanosome fractions from stage I to stage IV (PubMed:10636893).
Colocalizes with MTTP in the endoplasmic reticulum (PubMed:23475612).
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Cole-Carpenter syndrome 1 (CLCRP1)
- Note
- DescriptionA form of Cole-Carpenter syndrome, a disorder characterized by features of osteogenesis imperfecta such as bone deformities and severe bone fragility with frequent fractures, in association with craniosynostosis, ocular proptosis, hydrocephalus, growth failure and distinctive facial features. Craniofacial findings include marked frontal bossing, midface hypoplasia, and micrognathia. Despite the craniosynostosis and hydrocephalus, intellectual development is normal. CLCRP1 inheritance is autosomal dominant.
- See alsoMIM:112240
Natural variants in CLCRP1
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_073440 | 393 | Y>C | in CLCRP1; impairs ability to act as a disulfide isomerase enzyme; dbSNP:rs786204843 |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 128 | Reduced interaction with ERN1. Abolishes interaction with ERN1; when associated with W-403. | ||||
Sequence: W → I | ||||||
Mutagenesis | 331 | Phosphomimetic mutant. Does not affect enzyme or chaperone activity. | ||||
Sequence: S → E | ||||||
Mutagenesis | 357 | Abolishes phosphorylation at this site but protein is still phosphorylated at other sites. No changes in chaperone or enzyme activity. | ||||
Sequence: S → A | ||||||
Mutagenesis | 357 | Phosphomimetic mutant. Reduced resistance to protease digestion, sugesting adoption of an open conformation. Increased chaperone activity. Decreased enzyme activity. Increased binding to ERN1. | ||||
Sequence: S → E | ||||||
Natural variant | VAR_073440 | 393 | in CLCRP1; impairs ability to act as a disulfide isomerase enzyme; dbSNP:rs786204843 | |||
Sequence: Y → C | ||||||
Mutagenesis | 403 | Reduced interaction with ERN1. Abolishes interaction with ERN1; when associated with I-128. | ||||
Sequence: L → W | ||||||
Mutagenesis | 427 | Phosphomimetic mutant. Does not affect enzyme or chaperone activity. Does not increase binding to ERN1. | ||||
Sequence: S → E |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 563 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, modified residue (large scale data), disulfide bond, modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Signal | 1-17 | UniProt | |||||
Sequence: MLRRALLCLAVAALVRA | |||||||
Chain | PRO_0000034195 | 18-508 | UniProt | Protein disulfide-isomerase | |||
Sequence: DAPEEEDHVLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIKFFRNGDTASPKEYTAGREADDIVNWLKKRTGPAATTLPDGAAAESLVESSEVAVIGFFKDVESDSAKQFLQAAEAIDDIPFGITSNSDVFSKYQLDKDGVVLFKKFDEGRNNFEGEVTKENLLDFIKHNQLPLVIEFTEQTAPKIFGGEIKTHILLFLPKSVSDYDGKLSNFKTAAESFKGKILFIFIDSDHTDNQRILEFFGLKKEECPAVRLITLEEEMTKYKPESEELTAERITEFCHRFLEGKIKPHLMSQELPEDWDKQPVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVKVHSFPTLKFFPASADRTVIDYNGERTLDGFKKFLESGGQDGAGDDDDLEDLEEAEEPDMEEDDDQKAVKDEL | |||||||
Modified residue (large scale data) | 32 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Disulfide bond | 53↔56 | UniProt | Redox-active | ||||
Sequence: CGHC | |||||||
Modified residue (large scale data) | 88 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 101 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 200 | UniProt | N6-acetyllysine | ||||
Sequence: K | |||||||
Modified residue | 222 | UniProt | N6-succinyllysine | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 255 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 271 | UniProt | N6-succinyllysine | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 273 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 281 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 331 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 331 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 357 | UniProt | Phosphoserine; by FAM20C | ||||
Sequence: S | |||||||
Disulfide bond | 397↔400 | UniProt | Redox-active | ||||
Sequence: CGHC | |||||||
Modified residue | 427 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 427 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 439 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylation of Ser-357 by FAM20C is induced by endoplasmic reticulum stress and results in a functional switch from oxidoreductase to molecular chaperone (PubMed:32149426).
It also promotes interaction with ERN1 (PubMed:32149426).
It also promotes interaction with ERN1 (PubMed:32149426).
Keywords
- PTM
Proteomic databases
2D gel databases
PTM databases
Expression
Interaction
Subunit
Heterodimer; heterodimerizes with the protein microsomal triglyceride transfer MTTP (PubMed:16478722, PubMed:23475612, PubMed:26224785).
Homodimer. Monomers and homotetramers may also occur. Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen (PubMed:7753822).
Also constitutes the structural subunit of the microsomal triacylglycerol transfer protein MTTP in mammalian cells. Stabilizes both enzymes and retain them in the ER without contributing to the catalytic activity (By similarity).
Binds UBQLN1 (PubMed:12095988).
Interacts with ERO1B (PubMed:11707400).
Binds to CD4, and upon HIV-1 binding to the cell membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex. Interacts with ILDR2 (By similarity).
Interacts with ERN1/IRE1A (via N-terminus); the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (PubMed:32149426).
Homodimer. Monomers and homotetramers may also occur. Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen (PubMed:7753822).
Also constitutes the structural subunit of the microsomal triacylglycerol transfer protein MTTP in mammalian cells. Stabilizes both enzymes and retain them in the ER without contributing to the catalytic activity (By similarity).
Binds UBQLN1 (PubMed:12095988).
Interacts with ERO1B (PubMed:11707400).
Binds to CD4, and upon HIV-1 binding to the cell membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex. Interacts with ILDR2 (By similarity).
Interacts with ERN1/IRE1A (via N-terminus); the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (PubMed:32149426).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 18-134 | Thioredoxin 1 | ||||
Sequence: DAPEEEDHVLVLRKSNFAEALAAHKYLLVEFYAPWCGHCKALAPEYAKAAGKLKAEGSEIRLAKVDATEESDLAQQYGVRGYPTIKFFRNGDTASPKEYTAGREADDIVNWLKKRTG | ||||||
Domain | 349-475 | Thioredoxin 2 | ||||
Sequence: GKIKPHLMSQELPEDWDKQPVKVLVGKNFEDVAFDEKKNVFVEFYAPWCGHCKQLAPIWDKLGETYKDHENIVIAKMDSTANEVEAVKVHSFPTLKFFPASADRTVIDYNGERTLDGFKKFLESGGQ | ||||||
Region | 471-508 | Disordered | ||||
Sequence: ESGGQDGAGDDDDLEDLEEAEEPDMEEDDDQKAVKDEL | ||||||
Compositional bias | 476-508 | Acidic residues | ||||
Sequence: DGAGDDDDLEDLEEAEEPDMEEDDDQKAVKDEL | ||||||
Motif | 505-508 | Prevents secretion from ER | ||||
Sequence: KDEL |
Sequence similarities
Belongs to the protein disulfide isomerase family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length508
- Mass (Da)57,116
- Last updated1997-11-01 v3
- Checksum906CE6D9900B8FCE
Computationally mapped potential isoform sequences
There are 31 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A7P0T9D6 | A0A7P0T9D6_HUMAN | P4HB | 521 | ||
A0A7P0T9E3 | A0A7P0T9E3_HUMAN | P4HB | 74 | ||
A0A7P0T9K9 | A0A7P0T9K9_HUMAN | P4HB | 439 | ||
A0A7P0T9S9 | A0A7P0T9S9_HUMAN | P4HB | 135 | ||
A0A7P0T9U6 | A0A7P0T9U6_HUMAN | P4HB | 486 | ||
A0A7P0T8C0 | A0A7P0T8C0_HUMAN | P4HB | 481 | ||
A0A7P0T8J3 | A0A7P0T8J3_HUMAN | P4HB | 488 | ||
A0A7P0T940 | A0A7P0T940_HUMAN | P4HB | 66 | ||
A0A7P0T8X1 | A0A7P0T8X1_HUMAN | P4HB | 479 | ||
H0Y3Z3 | H0Y3Z3_HUMAN | P4HB | 418 | ||
A0A7P0TAX9 | A0A7P0TAX9_HUMAN | P4HB | 222 | ||
A0A7P0TBA3 | A0A7P0TBA3_HUMAN | P4HB | 59 | ||
A0A7P0TBP8 | A0A7P0TBP8_HUMAN | P4HB | 123 | ||
A0A7P0TA35 | A0A7P0TA35_HUMAN | P4HB | 542 | ||
A0A7P0TA71 | A0A7P0TA71_HUMAN | P4HB | 557 | ||
A0A7P0TA97 | A0A7P0TA97_HUMAN | P4HB | 479 | ||
A0A7P0TB26 | A0A7P0TB26_HUMAN | P4HB | 533 | ||
H7BZ94 | H7BZ94_HUMAN | P4HB | 464 | ||
A0A7P0Z4J0 | A0A7P0Z4J0_HUMAN | P4HB | 270 | ||
A0A7P0Z4S2 | A0A7P0Z4S2_HUMAN | P4HB | 304 | ||
A0A7P0Z476 | A0A7P0Z476_HUMAN | P4HB | 126 | ||
A0A7P0Z4B2 | A0A7P0Z4B2_HUMAN | P4HB | 62 | ||
A0A7P0Z4F8 | A0A7P0Z4F8_HUMAN | P4HB | 48 | ||
I3NI03 | I3NI03_HUMAN | P4HB | 118 | ||
B3KTQ9 | B3KTQ9_HUMAN | P4HB | 185 | ||
I3L514 | I3L514_HUMAN | P4HB | 463 | ||
I3L4M2 | I3L4M2_HUMAN | P4HB | 537 | ||
I3L3U6 | I3L3U6_HUMAN | P4HB | 128 | ||
I3L3P5 | I3L3P5_HUMAN | P4HB | 472 | ||
I3L1Y5 | I3L1Y5_HUMAN | P4HB | 54 | ||
I3L0S0 | I3L0S0_HUMAN | P4HB | 466 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 10-11 | in Ref. 1; CAA28775 | ||||
Sequence: AV → PW | ||||||
Sequence conflict | 21 | in Ref. 13; AA sequence | ||||
Sequence: E → D | ||||||
Sequence conflict | 24 | in Ref. 13; AA sequence | ||||
Sequence: D → V | ||||||
Sequence conflict | 44-45 | in Ref. 1; CAA28775 | ||||
Sequence: LL → PP | ||||||
Sequence conflict | 49 | in Ref. 1; CAA28775 | ||||
Sequence: Y → H | ||||||
Sequence conflict | 141 | in Ref. 2; AAA61169 | ||||
Sequence: P → R | ||||||
Sequence conflict | 360-362 | in Ref. 2; AAA61169 | ||||
Sequence: LPE → RAG | ||||||
Sequence conflict | 372 | in Ref. 2; AAA61169 | ||||
Sequence: L → P | ||||||
Sequence conflict | 439 | in Ref. 1; CAA28775 | ||||
Sequence: S → G | ||||||
Sequence conflict | 444 | in Ref. 1; CAA28775 | ||||
Sequence: K → G | ||||||
Sequence conflict | 460 | in Ref. 15; CAA30112 | ||||
Sequence: E → Q | ||||||
Compositional bias | 476-508 | Acidic residues | ||||
Sequence: DGAGDDDDLEDLEEAEEPDMEEDDDQKAVKDEL | ||||||
Sequence conflict | 481 | in Ref. 1; CAA28775 | ||||
Sequence: D → V |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
X05130 EMBL· GenBank· DDBJ | CAA28775.1 EMBL· GenBank· DDBJ | mRNA | ||
J02783 EMBL· GenBank· DDBJ | AAA61169.1 EMBL· GenBank· DDBJ | mRNA | ||
M22806 EMBL· GenBank· DDBJ | AAC13652.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M22803 EMBL· GenBank· DDBJ | AAC13652.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M22804 EMBL· GenBank· DDBJ | AAC13652.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M22805 EMBL· GenBank· DDBJ | AAC13652.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK315631 EMBL· GenBank· DDBJ | BAG37999.1 EMBL· GenBank· DDBJ | mRNA | ||
CH471099 EMBL· GenBank· DDBJ | EAW89690.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC010859 EMBL· GenBank· DDBJ | AAH10859.1 EMBL· GenBank· DDBJ | mRNA | ||
BC029617 EMBL· GenBank· DDBJ | AAH29617.1 EMBL· GenBank· DDBJ | mRNA | ||
BC071892 EMBL· GenBank· DDBJ | AAH71892.1 EMBL· GenBank· DDBJ | mRNA | ||
S37207 EMBL· GenBank· DDBJ | AAB22262.2 EMBL· GenBank· DDBJ | Genomic DNA | ||
X07077 EMBL· GenBank· DDBJ | CAA30112.1 EMBL· GenBank· DDBJ | mRNA |