P19447 · ERCC3_HUMAN
- ProteinGeneral transcription and DNA repair factor IIH helicase/translocase subunit XPB
- GeneERCC3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids782 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
ATP-dependent 3'-5' DNA helicase/translocase (PubMed:17466626, PubMed:27193682, PubMed:33902107, PubMed:8465201, PubMed:8663148).
Binds dsDNA rather than ssDNA, unzipping it in a translocase rather than classical helicase activity (PubMed:27193682, PubMed:33902107).
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex (PubMed:10024882, PubMed:17466626, PubMed:8157004, PubMed:8465201).
When complexed to CDK-activating kinase (CAK), involved in RNA transcription by RNA polymerase II. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening; it may wrap around the damaged DNA wedging it open, causing localized melting that allows XPD/ERCC2 helicase to anchor (PubMed:10024882, PubMed:17466626).
In transcription, TFIIH has an essential role in transcription initiation (PubMed:30894545, PubMed:8157004).
When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape (PubMed:8157004).
The ATP-dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape (PubMed:10024882).
In transcription pre-initiation complexes induces and propagates a DNA twist to open DNA (PubMed:27193682, PubMed:33902107).
Also involved in transcription-coupled nucleotide excision repair (NER) of damaged DNA (PubMed:17466626, PubMed:2111438, PubMed:8157004).
In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The structure of the TFIIH transcription complex differs from the NER-TFIIH complex; large movements by XPD/ERCC2 and XPB/ERCC3 are stabilized by XPA (PubMed:31253769, PubMed:33902107).
XPA retains XPB/ERCC3 at the 5' end of a DNA bubble (mimicking DNA damage) (PubMed:31253769).
Binds dsDNA rather than ssDNA, unzipping it in a translocase rather than classical helicase activity (PubMed:27193682, PubMed:33902107).
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex (PubMed:10024882, PubMed:17466626, PubMed:8157004, PubMed:8465201).
When complexed to CDK-activating kinase (CAK), involved in RNA transcription by RNA polymerase II. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening; it may wrap around the damaged DNA wedging it open, causing localized melting that allows XPD/ERCC2 helicase to anchor (PubMed:10024882, PubMed:17466626).
In transcription, TFIIH has an essential role in transcription initiation (PubMed:30894545, PubMed:8157004).
When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape (PubMed:8157004).
The ATP-dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape (PubMed:10024882).
In transcription pre-initiation complexes induces and propagates a DNA twist to open DNA (PubMed:27193682, PubMed:33902107).
Also involved in transcription-coupled nucleotide excision repair (NER) of damaged DNA (PubMed:17466626, PubMed:2111438, PubMed:8157004).
In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The structure of the TFIIH transcription complex differs from the NER-TFIIH complex; large movements by XPD/ERCC2 and XPB/ERCC3 are stabilized by XPA (PubMed:31253769, PubMed:33902107).
XPA retains XPB/ERCC3 at the 5' end of a DNA bubble (mimicking DNA damage) (PubMed:31253769).
Miscellaneous
The TFIIH core complex from patient XP11BE (a patient with XP/CS who has a C-terminal splice-site frameshift from residue 741 in this protein) reconstitutes in vitro transcription about 30% less well than wild-type but does not restore NER in vitro or in vivo (PubMed:8663148).
The XP11BE TFIIH complex has all the subunits in the same stoichiometry as wild-type (PubMed:8663148).
Purified mutant protein has very weak 3'-5' helicase and ATPase activities (PubMed:8663148).
In another paper the mutant protein has wild-type 3'-5' helicase activity (PubMed:15549133).
The mutation is recessive to wild-type (PubMed:2167179, PubMed:8663148).
XPB/ERCC3 is not phosphorylated in vitro in this mutant, and does not restore transcription in XPB/ERCC3-defective cells (PubMed:15549133).
The XP11BE TFIIH complex has all the subunits in the same stoichiometry as wild-type (PubMed:8663148).
Purified mutant protein has very weak 3'-5' helicase and ATPase activities (PubMed:8663148).
In another paper the mutant protein has wild-type 3'-5' helicase activity (PubMed:15549133).
The mutation is recessive to wild-type (PubMed:2167179, PubMed:8663148).
XPB/ERCC3 is not phosphorylated in vitro in this mutant, and does not restore transcription in XPB/ERCC3-defective cells (PubMed:15549133).
Conventional DNA helicases unwind DNA by binding to a ssDNA overhang of dsDNA and then translocating on this strand with cycles of ATP binding and hydrolysis to 'unzip' the dsDNA. XPB/ERCC3 is believed to be an unconventional DNA helicase principally because it translocates in a 3'-5' direction along dsDNA instead of ssDNA, thus it is referred to as a DNA translocase (PubMed:27193682, PubMed:33902107).
Catalytic activity
- ATP + H2O = ADP + H+ + phosphate
Activity regulation
Phosphorylation on Ser-751 by CK2 controls the 5'-excision activity of ERCC1-XPF endonuclease; phosphorylated protein inhibits the excision activity and thus NER (PubMed:15549133).
ATPase activity is stimulated by TFIIH subunit p52 (GTF2H4) (PubMed:17466626).
DNA translocase activity by this subunit in TFIIH is stimulated by XPA, ERCC5/XPG and XFP plus ERCC1; translocase activity is sensitive to triptolide which targets this enzyme (PubMed:31253769).
ATPase activity is stimulated by TFIIH subunit p52 (GTF2H4) (PubMed:17466626).
DNA translocase activity by this subunit in TFIIH is stimulated by XPA, ERCC5/XPG and XFP plus ERCC1; translocase activity is sensitive to triptolide which targets this enzyme (PubMed:31253769).
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameGeneral transcription and DNA repair factor IIH helicase/translocase subunit XPB
- EC number
- Short namesTFIIH subunit XPB
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP19447
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Involvement in disease
Xeroderma pigmentosum complementation group B (XP-B)
- Note
- DescriptionAn autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. Some XP-B patients present features of Cockayne syndrome, including cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex.
- See alsoMIM:610651
Natural variants in XP-B
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_003632 | 99 | F>S | in XP-B; combined with features of Cockayne syndrome; mild; reduced interaction with GTF2H4/p52 leads to low ATPase stimulation and decreased DNA duplex unwinding by TFIIH; does not alter helicase activity; does not alter TFIIH recruitment to DNA damage; XPA is not recruited to DNA damage by TFIIH; nearly wild-type transcription activity by TFIIH; dbSNP:rs121913045 |
Trichothiodystrophy 2, photosensitive (TTD2)
- Note
- DescriptionA form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder.
- See alsoMIM:616390
Natural variants in TTD2
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_008186 | 119 | T>P | in TTD2; mild; wild-type dual incision, opening around damaged DNA and transcription by TFIIH; dbSNP:rs121913046 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_003632 | 99 | in XP-B; combined with features of Cockayne syndrome; mild; reduced interaction with GTF2H4/p52 leads to low ATPase stimulation and decreased DNA duplex unwinding by TFIIH; does not alter helicase activity; does not alter TFIIH recruitment to DNA damage; XPA is not recruited to DNA damage by TFIIH; nearly wild-type transcription activity by TFIIH; dbSNP:rs121913045 | |||
Sequence: F → S | ||||||
Natural variant | VAR_014766 | 117 | in dbSNP:rs1805161 | |||
Sequence: K → R | ||||||
Natural variant | VAR_008186 | 119 | in TTD2; mild; wild-type dual incision, opening around damaged DNA and transcription by TFIIH; dbSNP:rs121913046 | |||
Sequence: T → P | ||||||
Mutagenesis | 346 | Dominant-negative effect on transcription and NER, induces chromatin collapse, probably has no ATPase activity. No transcriptional activity of the reconstituted TFIIH complex. TFHHI is inactive in DNA repair and in transcription. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_014767 | 402 | in dbSNP:rs1805162 | |||
Sequence: G → C | ||||||
Natural variant | VAR_035942 | 418 | in a breast cancer sample; somatic mutation | |||
Sequence: K → Q | ||||||
Mutagenesis | 469 | Very low 3'-5' helicase activity, wild-type ATPase activity, opens damaged DNA, nearly wild-type NER activity in vivo, 50% decreased transcription in vitro. | ||||
Sequence: T → A | ||||||
Mutagenesis | 638 | Very low 3'-5' helicase activity, wild-type ATPase activity, wild-type damaged DNA removal, 80% decreased transcription (all in vitro). | ||||
Sequence: Q → A | ||||||
Natural variant | VAR_017294 | 704 | in dbSNP:rs4150521 | |||
Sequence: S → L | ||||||
Natural variant | VAR_014344 | 735 | in dbSNP:rs4150522 | |||
Sequence: S → P | ||||||
Mutagenesis | 751 | Restores NER in XPB/ERCC3-defective cells, does not inhibit 5'-incision by ERCC1-XPF, wild-type transcription and helicase activities. | ||||
Sequence: S → A | ||||||
Mutagenesis | 751 | Does not restore NER in XPB/ERCC3-defective cells, inhibits 5'-incision by ERCC1-XPF, wild-type transcription and helicase activities. | ||||
Sequence: S → E | ||||||
Mutagenesis | 782 | Impairs protein folding. | ||||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 1,123 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 chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000101987 | 1-782 | UniProt | General transcription and DNA repair factor IIH helicase/translocase subunit XPB | |||
Sequence: MGKRDRADRDKKKSRKRHYEDEEDDEEDAPGNDPQEAVPSAAGKQVDESGTKVDEYGAKDYRLQMPLKDDHTSRPLWVAPDGHIFLEAFSPVYKYAQDFLVAIAEPVCRPTHVHEYKLTAYSLYAAVSVGLQTSDITEYLRKLSKTGVPDGIMQFIKLCTVSYGKVKLVLKHNRYFVESCHPDVIQHLLQDPVIRECRLRNSEGEATELITETFTSKSAISKTAESSGGPSTSRVTDPQGKSDIPMDLFDFYEQMDKDEEEEEETQTVSFEVKQEMIEELQKRCIHLEYPLLAEYDFRNDSVNPDINIDLKPTAVLRPYQEKSLRKMFGNGRARSGVIVLPCGAGKSLVGVTAACTVRKRCLVLGNSAVSVEQWKAQFKMWSTIDDSQICRFTSDAKDKPIGCSVAISTYSMLGHTTKRSWEAERVMEWLKTQEWGLMILDEVHTIPAKMFRRVLTIVQAHCKLGLTATLVREDDKIVDLNFLIGPKLYEANWMELQNNGYIAKVQCAEVWCPMSPEFYREYVAIKTKKRILLYTMNPNKFRACQFLIKFHERRNDKIIVFADNVFALKEYAIRLNKPYIYGPTSQGERMQILQNFKHNPKINTIFISKVGDTSFDLPEANVLIQISSHGGSRRQEAQRLGRVLRAKKGMVAEEYNAFFYSLVSQDTQEMAYSTKRQRFLVDQGYSFKVITKLAGMEEEDLAFSTKEEQQQLLQKVLAATDLDAEEEVVAGEFGSRSSQASRRFGTMSSMSGADDTVYMEYHSSRSKAPSKHVHPLFKRFRK | |||||||
Modified residue (large scale data) | 202 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 236 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 686 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 686 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 751 | UniProt | Phosphoserine; by CK2 | ||||
Sequence: S |
Post-translational modification
Phosphorylation on Ser-751 by CK2 controls the 5'-excision activity of ERCC1-XPF endonuclease; phosphorylated protein inhibits the excision activity and thus NER (PubMed:15549133).
Dephosphorylation reactivates the 5'-excision step (PubMed:15549133).
Phosphorylation has no effect on transcription or the 3'-5' helicase activity (PubMed:15549133).
Dephosphorylation reactivates the 5'-excision step (PubMed:15549133).
Phosphorylation has no effect on transcription or the 3'-5' helicase activity (PubMed:15549133).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:8663148, PubMed:9852112).
Interacts with PUF60 (PubMed:10882074, PubMed:11239393).
Interacts with ATF7IP (PubMed:19106100).
Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones (PubMed:30894545).
Part of TBP-based Pol II pre-initiation complex (PIC), in which Pol II core assembles with general transcription factors and other specific initiation factors including GTF2E1, GTF2E2, GTF2F1, GTF2F2, TCEA1, ERCC2, ERCC3, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2A1, GTF2A2, GTF2B and TBP; this large multi-subunit PIC complex mediates DNA unwinding and targets Pol II core to the transcription start site where the first phosphodiester bond forms
Interacts with PUF60 (PubMed:10882074, PubMed:11239393).
Interacts with ATF7IP (PubMed:19106100).
Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones (PubMed:30894545).
Part of TBP-based Pol II pre-initiation complex (PIC), in which Pol II core assembles with general transcription factors and other specific initiation factors including GTF2E1, GTF2E2, GTF2F1, GTF2F2, TCEA1, ERCC2, ERCC3, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2A1, GTF2A2, GTF2B and TBP; this large multi-subunit PIC complex mediates DNA unwinding and targets Pol II core to the transcription start site where the first phosphodiester bond forms
(Microbial infection) Interacts with Epstein-Barr virus EBNA2.
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for compositional bias, region, motif, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 1-22 | Basic and acidic residues | ||||
Sequence: MGKRDRADRDKKKSRKRHYEDE | ||||||
Region | 1-51 | Disordered | ||||
Sequence: MGKRDRADRDKKKSRKRHYEDEEDDEEDAPGNDPQEAVPSAAGKQVDESGT | ||||||
Motif | 6-18 | Nuclear localization signal | ||||
Sequence: RADRDKKKSRKRH | ||||||
Compositional bias | 218-239 | Polar residues | ||||
Sequence: SAISKTAESSGGPSTSRVTDPQ | ||||||
Region | 218-241 | Disordered | ||||
Sequence: SAISKTAESSGGPSTSRVTDPQGK | ||||||
Domain | 327-488 | Helicase ATP-binding | ||||
Sequence: MFGNGRARSGVIVLPCGAGKSLVGVTAACTVRKRCLVLGNSAVSVEQWKAQFKMWSTIDDSQICRFTSDAKDKPIGCSVAISTYSMLGHTTKRSWEAERVMEWLKTQEWGLMILDEVHTIPAKMFRRVLTIVQAHCKLGLTATLVREDDKIVDLNFLIGPKL | ||||||
Motif | 441-444 | DEVH box | ||||
Sequence: DEVH | ||||||
Domain | 542-702 | Helicase C-terminal | ||||
Sequence: RACQFLIKFHERRNDKIIVFADNVFALKEYAIRLNKPYIYGPTSQGERMQILQNFKHNPKINTIFISKVGDTSFDLPEANVLIQISSHGGSRRQEAQRLGRVLRAKKGMVAEEYNAFFYSLVSQDTQEMAYSTKRQRFLVDQGYSFKVITKLAGMEEEDLA |
Sequence similarities
Belongs to the helicase family. RAD25/XPB subfamily.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length782
- Mass (Da)89,278
- Last updated1991-02-01 v1
- ChecksumF5F4D3A89A7DF826
Computationally mapped potential isoform sequences
There are 10 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A2R8Y6W8 | A0A2R8Y6W8_HUMAN | ERCC3 | 807 | ||
A0A2R8Y762 | A0A2R8Y762_HUMAN | ERCC3 | 216 | ||
A0A2R8Y681 | A0A2R8Y681_HUMAN | ERCC3 | 162 | ||
A0A2R8Y5L2 | A0A2R8Y5L2_HUMAN | ERCC3 | 448 | ||
A0A2R8Y5H0 | A0A2R8Y5H0_HUMAN | ERCC3 | 160 | ||
A0A2R8Y4R8 | A0A2R8Y4R8_HUMAN | ERCC3 | 122 | ||
A0A2R8YFS3 | A0A2R8YFS3_HUMAN | ERCC3 | 161 | ||
A0A2R8YES7 | A0A2R8YES7_HUMAN | ERCC3 | 406 | ||
H7C309 | H7C309_HUMAN | ERCC3 | 188 | ||
F2Z2V4 | F2Z2V4_HUMAN | ERCC3 | 71 |
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 1-22 | Basic and acidic residues | ||||
Sequence: MGKRDRADRDKKKSRKRHYEDE | ||||||
Compositional bias | 218-239 | Polar residues | ||||
Sequence: SAISKTAESSGGPSTSRVTDPQ |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M31899 EMBL· GenBank· DDBJ | AAA52396.1 EMBL· GenBank· DDBJ | mRNA | ||
AY163769 EMBL· GenBank· DDBJ | AAN46739.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AC110926 EMBL· GenBank· DDBJ | AAY15069.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471103 EMBL· GenBank· DDBJ | EAW95313.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC008820 EMBL· GenBank· DDBJ | AAH08820.1 EMBL· GenBank· DDBJ | mRNA |