Q9UNE7 · CHIP_HUMAN
- ProteinE3 ubiquitin-protein ligase CHIP
- GeneSTUB1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids303 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Plays a role in the maintenance of mitochondrial morphology and promotes mitophagic removal of dysfunctional mitochondria; thereby acts as a protector against apoptosis in response to cellular stress (By similarity).
Negatively regulates vascular smooth muscle contraction, via degradation of the transcriptional activator MYOCD and subsequent loss of transcription of genes involved in vascular smooth muscle contraction (By similarity).
Promotes survival and proliferation of cardiac smooth muscle cells via ubiquitination and degradation of FOXO1, resulting in subsequent repression of FOXO1-mediated transcription of pro-apoptotic genes (PubMed:19483080).
Ubiquitinates ICER-type isoforms of CREM and targets them for proteasomal degradation, thereby acts as a positive effector of MAPK/ERK-mediated inhibition of apoptosis in cardiomyocytes (PubMed:20724525).
Inhibits lipopolysaccharide-induced apoptosis and hypertrophy in cardiomyocytes, via ubiquitination and subsequent proteasomal degradation of NFATC3 (PubMed:30980393).
Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (PubMed:10330192, PubMed:11146632, PubMed:11557750, PubMed:23990462).
Ubiquitinates NOS1 in concert with Hsp70 and Hsp40 (PubMed:15466472).
Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90 (PubMed:10330192, PubMed:11146632, PubMed:15466472).
Ubiquitinates CHRNA3 targeting it for endoplasmic reticulum-associated degradation in cortical neurons, as part of the STUB1-VCP-UBXN2A complex (PubMed:26265139).
Ubiquitinates and promotes ESR1 proteasomal degradation in response to age-related circulating estradiol (17-beta-estradiol/E2) decline, thereby promotes neuronal apoptosis in response to ischemic reperfusion injury (By similarity).
Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation (PubMed:11557750, PubMed:23990462).
Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome (PubMed:19713937).
Mediates polyubiquitination of CYP3A4 (PubMed:19103148).
Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation (PubMed:19567782).
Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation (PubMed:27708256).
Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner (PubMed:23973223).
Catalyzes monoubiquitination of SIRT6, preventing its degradation by the proteasome (PubMed:24043303).
Likely mediates polyubiquitination and down-regulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity (PubMed:28813410).
Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385).
Plays a role in the degradation of TP53 (PubMed:26634371).
Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).
May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820).
Miscellaneous
Catalytic activity
Pathway
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
CHIP signals CDK4 degradation in response to endoplasmic reticulum stress.
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase CHIP
- EC number
- Alternative names
Gene names
- Community suggested namesCHIP
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9UNE7
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Spinocerebellar ataxia, autosomal recessive, 16 (SCAR16)
- Note
- DescriptionA form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR16 is characterized by truncal and limb ataxia resulting in gait instability. Additionally, patients may show dysarthria, nystagmus, spasticity of the lower limbs, and mild peripheral sensory neuropathy.
- See alsoMIM:615768
Natural variants in SCAR16
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_072348 | 28 | E>K | in SCAR16; reduces protein level; does not reduce ubiquitin ligase activity and autoubiquitination | |
VAR_072349 | 65 | N>S | in SCAR16; reduces protein level; reduces ubiquitin ligase activity; does not change autoubiquitination; dbSNP:rs690016544 | |
VAR_071293 | 79 | A>D | in SCAR16; dbSNP:rs587777347 | |
VAR_071294 | 79 | A>T | in SCAR16; dbSNP:rs587777346 | |
VAR_071295 | 123 | L>V | in SCAR16; dbSNP:rs587777344 | |
VAR_071296 | 130 | N>I | in SCAR16; dbSNP:rs587777341 | |
VAR_072350 | 145 | K>Q | in SCAR16; dbSNP:rs146251364 | |
VAR_071297 | 147 | W>C | in SCAR16; dbSNP:rs587777342 | |
VAR_071298 | 165 | L>F | in SCAR16; dbSNP:rs587777340 | |
VAR_071299 | 236 | S>T | in SCAR16; dbSNP:rs2039692794 | |
VAR_071300 | 240 | M>T | in SCAR16; dbSNP:rs587777345 | |
VAR_071301 | 246 | T>M | in SCAR16; inhibits ubiquitin ligase activity and autoubiquitination; dbSNP:rs587777343 |
Spinocerebellar ataxia 48 (SCA48)
- Note
- DescriptionA form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA48 is an autosomal dominant neurodegenerative disease characterized by onset in mid-adulthood of progressive cognitive decline and gait ataxia, and vermian and hemispheric cerebellar atrophy.
- See alsoMIM:618093
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_072348 | 28 | in SCAR16; reduces protein level; does not reduce ubiquitin ligase activity and autoubiquitination | |||
Sequence: E → K | ||||||
Mutagenesis | 30 | Loss of interaction with FOXP3 and its ability to ubiquitinate FOXP3. Loss of interaction with SMAD3, HSPA8, HSP90AA1 and HSP90AB1. Reduces interaction, ubiquitination and proteasomal degradation of NFATC3. No effect on localization to the mitochondria following oxygen and glucose deprivation-induced cellular stress. | ||||
Sequence: K → A | ||||||
Natural variant | VAR_085041 | 57 | found in a patient with progressive myoclonus epilepsy; uncertain significance | |||
Sequence: P → S | ||||||
Natural variant | VAR_072349 | 65 | in SCAR16; reduces protein level; reduces ubiquitin ligase activity; does not change autoubiquitination; dbSNP:rs690016544 | |||
Sequence: N → S | ||||||
Natural variant | VAR_071293 | 79 | in SCAR16; dbSNP:rs587777347 | |||
Sequence: A → D | ||||||
Natural variant | VAR_071294 | 79 | in SCAR16; dbSNP:rs587777346 | |||
Sequence: A → T | ||||||
Natural variant | VAR_071295 | 123 | in SCAR16; dbSNP:rs587777344 | |||
Sequence: L → V | ||||||
Natural variant | VAR_071296 | 130 | in SCAR16; dbSNP:rs587777341 | |||
Sequence: N → I | ||||||
Natural variant | VAR_072350 | 145 | in SCAR16; dbSNP:rs146251364 | |||
Sequence: K → Q | ||||||
Natural variant | VAR_071297 | 147 | in SCAR16; dbSNP:rs587777342 | |||
Sequence: W → C | ||||||
Natural variant | VAR_071298 | 165 | in SCAR16; dbSNP:rs587777340 | |||
Sequence: L → F | ||||||
Natural variant | VAR_071299 | 236 | in SCAR16; dbSNP:rs2039692794 | |||
Sequence: S → T | ||||||
Natural variant | VAR_071300 | 240 | in SCAR16; dbSNP:rs587777345 | |||
Sequence: M → T | ||||||
Natural variant | VAR_071301 | 246 | in SCAR16; inhibits ubiquitin ligase activity and autoubiquitination; dbSNP:rs587777343 | |||
Sequence: T → M | ||||||
Mutagenesis | 260 | Loss of ability to ubiquitinate FOXP3 and SIRT6. Abolishes STUB1-mediated degradation of CHRNA3. Abolishes autoubiquitination and ubiquitination of ICER-type isoforms of CREM. Reduces interaction, ubiquitination and proteasomal degradation of NFATC3. No effect on localization to the mitochondria following oxygen and glucose deprivation-induced cellular stress. | ||||
Sequence: H → Q | ||||||
Mutagenesis | 269 | Abolishes E3 ligase activity. | ||||
Sequence: P → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 374 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, cross-link, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000106329 | 1-303 | UniProt | E3 ubiquitin-protein ligase CHIP | |||
Sequence: MKGKEEKEGGARLGAGGGSPEKSPSAQELKEQGNRLFVGRKYPEAAACYGRAITRNPLVAVYYTNRALCYLKMQQHEQALADCRRALELDGQSVKAHFFLGQCQLEMESYDEAIANLQRAYSLAKEQRLNFGDDIPSALRIAKKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDEDDSHVRAQQACIEAKHDKYMADMDELFSQVDEKRKKRDIPDYLCGKISFELMREPCITPSGITYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLAMKEVIDAFISENGWVEDY | |||||||
Cross-link | 2 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 19 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 19 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 22 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 23 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 23 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 25 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 25 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 137 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 149 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 191 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 221 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 255 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 273 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 273 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 276 | PRIDE | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
Auto-ubiquitinated; mediated by UBE2D1 and UBE2D2 and enhanced in the presence of MAP2K5 (PubMed:20724525).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (PubMed:10330192, PubMed:11435423).
Detected in kidney, liver and lung (PubMed:10330192, PubMed:11435423).
Induction
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts with BAG2 (PubMed:16169850).
Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3 (PubMed:11557750).
Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (PubMed:15215316).
Part of a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that modulates the ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of CHRNA3 (PubMed:26265139).
Within the complex UBXN2A acts as a scaffold protein required for the interaction of CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 ubiquitination by STUB1/CHIP and subsequently ERAD (PubMed:26265139).
Interacts with MKKS (PubMed:18094050).
Interacts with DNAAF4 (PubMed:19423554).
Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity).
Interacts with DNAJB6 (PubMed:22366786).
Interacts with FLCN (PubMed:27353360).
Interacts with HSP90AA1 (PubMed:24613385, PubMed:27353360).
Interacts with HSP90 (PubMed:11146632).
Interacts with UBE2N and UBE2V1 (PubMed:16307917).
Interacts (via TPR repeats) with HSPA8 (via C-terminus) (PubMed:10330192, PubMed:11557750, PubMed:23990462, PubMed:27708256).
Interacts (via TPR repeats) with HSPA1A (via C-terminus) (PubMed:10330192).
Interacts with the non-acetylated form of HSPA1A and HSPA1B (PubMed:27708256).
Interacts with SMAD3 and HSP90AB1 (PubMed:24613385).
Interacts with UBE4B (PubMed:17369820).
Interacts with PRMT5 (PubMed:33376131).
Interacts with MYOCD (via C-terminus) (By similarity).
Interacts with FOXO1 (when phosphorylated on 'Ser-256') (PubMed:19483080).
Interacts with MAPK7/ERK5; the interaction is enhanced in the presence of IGF1 or MAP2K5 and promotes STUB1/CHIP E3 ligase activity (PubMed:20724525).
Interacts with and ubiquitinates ESR1; the interaction is promoted in the absence of estradiol (17-beta-estradiol/E2) (By similarity).
Interacts with ESR2 (By similarity).
Interacts with and ubiquitinates NFATC3; HSPA1A/HSP70 is required as a co-chaperone (PubMed:30980393).
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, repeat, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-30 | Disordered | ||||
Sequence: MKGKEEKEGGARLGAGGGSPEKSPSAQELK | ||||||
Repeat | 26-59 | TPR 1 | ||||
Sequence: AQELKEQGNRLFVGRKYPEAAACYGRAITRNPLV | ||||||
Repeat | 60-93 | TPR 2 | ||||
Sequence: AVYYTNRALCYLKMQQHEQALADCRRALELDGQS | ||||||
Repeat | 95-127 | TPR 3 | ||||
Sequence: KAHFFLGQCQLEMESYDEAIANLQRAYSLAKEQ | ||||||
Region | 101-200 | Required for interaction with MAPK7 | ||||
Sequence: GQCQLEMESYDEAIANLQRAYSLAKEQRLNFGDDIPSALRIAKKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDEDDSHVRAQQACI | ||||||
Region | 142-196 | Required for interaction with and ubiquitination of MYOCD | ||||
Sequence: AKKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDEDDSHVRAQ | ||||||
Region | 143-197 | Required for interaction with FOXO1 | ||||
Sequence: KKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDEDDSHVRAQQ | ||||||
Region | 143-303 | Required for ubiquitination of FOXO1 | ||||
Sequence: KKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDEDDSHVRAQQACIEAKHDKYMADMDELFSQVDEKRKKRDIPDYLCGKISFELMREPCITPSGITYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLAMKEVIDAFISENGWVEDY | ||||||
Domain | 226-300 | U-box | ||||
Sequence: DIPDYLCGKISFELMREPCITPSGITYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLAMKEVIDAFISENGWV |
Domain
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9UNE7-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length303
- Mass (Da)34,856
- Last updated2005-10-25 v2
- Checksum7E7D6568B17070BF
Q9UNE7-2
- Name2
- Differences from canonical
- 1-72: Missing
Computationally mapped potential isoform sequences
There are 4 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_015947 | 1-72 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 52 | in Ref. 2; AAD33400 | ||||
Sequence: A → V | ||||||
Sequence conflict | 272 | in Ref. 1; AAC18038 | ||||
Sequence: R → G | ||||||
Sequence conflict | 280 | in Ref. 1; AAC18038 | ||||
Sequence: L → F |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF039689 EMBL· GenBank· DDBJ | AAC18038.1 EMBL· GenBank· DDBJ | mRNA | ||
AF129085 EMBL· GenBank· DDBJ | AAD33400.1 EMBL· GenBank· DDBJ | mRNA | ||
AF432221 EMBL· GenBank· DDBJ | AAL99927.1 EMBL· GenBank· DDBJ | mRNA | ||
AF217968 EMBL· GenBank· DDBJ | AAG17211.1 EMBL· GenBank· DDBJ | mRNA | ||
AE006464 EMBL· GenBank· DDBJ | AAK61242.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Z92544 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471112 EMBL· GenBank· DDBJ | EAW85758.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC007545 EMBL· GenBank· DDBJ | AAH07545.1 EMBL· GenBank· DDBJ | mRNA | ||
BC017178 EMBL· GenBank· DDBJ | AAH17178.1 EMBL· GenBank· DDBJ | mRNA | ||
BC022788 EMBL· GenBank· DDBJ | AAH22788.1 EMBL· GenBank· DDBJ | mRNA | ||
BC063617 EMBL· GenBank· DDBJ | AAH63617.1 EMBL· GenBank· DDBJ | mRNA |