Q8C7D2 · CRBN_MOUSE
- ProteinProtein cereblon
- GeneCrbn
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids445 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2, ILF2 or GLUL. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8 (By similarity).
Maintains presynaptic glutamate release and consequently, cognitive functions such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons (PubMed:29530986).
Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (By similarity).
May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (PubMed:29530986).
Plays a negative role in TLR4 signaling by interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT ubiquitination, an important step of the signaling (By similarity).
Maintains presynaptic glutamate release and consequently, cognitive functions such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons (PubMed:29530986).
Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (By similarity).
May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (PubMed:29530986).
Plays a negative role in TLR4 signaling by interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT ubiquitination, an important step of the signaling (By similarity).
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 326 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 329 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 381 | (S)-thalidomide (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 383 | (S)-thalidomide (UniProtKB | ChEBI) | ||||
Sequence: W | ||||||
Binding site | 389 | (S)-thalidomide (UniProtKB | ChEBI) | ||||
Sequence: W | ||||||
Binding site | 394 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 397 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | Cul4A-RING E3 ubiquitin ligase complex | |
Cellular Component | cytoplasm | |
Cellular Component | membrane | |
Cellular Component | nucleus | |
Cellular Component | perinuclear region of cytoplasm | |
Molecular Function | metal ion binding | |
Molecular Function | transmembrane transporter binding | |
Biological Process | locomotory exploration behavior | |
Biological Process | negative regulation of large conductance calcium-activated potassium channel activity | |
Biological Process | negative regulation of monoatomic ion transmembrane transport | |
Biological Process | negative regulation of protein-containing complex assembly | |
Biological Process | positive regulation of protein-containing complex assembly | |
Biological Process | positive regulation of Wnt signaling pathway | |
Biological Process | proteasome-mediated ubiquitin-dependent protein catabolic process | |
Biological Process | protein ubiquitination |
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameProtein cereblon
- Short namesProtein PiL
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ8C7D2
- Secondary accessions
Proteomes
Organism-specific databases
Phenotypes & Variants
Disruption phenotype
No obvious phenotype, however mice display increased BK channel activity and a subsequent decrease in synaptic transmission and presynaptic release probability in excitatory synapses (PubMed:29530986).
Mice also display cognitive behavioral defects such as abnormal passive avoidance, hyperanxious behavior and decreased preference for new objects (PubMed:29530986).
Treatment with the BK blocker paxilline rescues all synaptic and behavioral abnormalities except for hyperanxiety (PubMed:29530986).
Brain and synaptic morphology is normal and long-term synaptic plasticity is not affected (PubMed:29530986).
Conditional knockout in the forebrain results in no obvious phenotype, however mice display a deficit in contextual fear learning whereas anxiety-like behavior is unaffected (PubMed:21995942).
Mice also display cognitive behavioral defects such as abnormal passive avoidance, hyperanxious behavior and decreased preference for new objects (PubMed:29530986).
Treatment with the BK blocker paxilline rescues all synaptic and behavioral abnormalities except for hyperanxiety (PubMed:29530986).
Brain and synaptic morphology is normal and long-term synaptic plasticity is not affected (PubMed:29530986).
Conditional knockout in the forebrain results in no obvious phenotype, however mice display a deficit in contextual fear learning whereas anxiety-like behavior is unaffected (PubMed:21995942).
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 8 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000076161 | 1-445 | Protein cereblon | |||
Sequence: MAGEGDQQDAAHNMGNHLPLLPADSEDEDDEIEMEVEDQDSKEARKPNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPEVLMILIPGQTLPLQLSHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQEFGIEVVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQVFPSKPISWEDQYSCKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPENPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKASNLNLIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTIPETEDEISPDKVILCL | ||||||
Modified residue | 25 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Ubiquitinated, ubiquitination is mediated by its own DCX protein ligase complex.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Highly expressed in brain.
Developmental stage
In brain, expression is abundant in the cerebellum, with less expression in the neocortical, hippocampus and striatum in adult. Neocortical expression increases from embryonic stages to adulthood.
Gene expression databases
Interaction
Subunit
Component of a DCX (DDB1-CUL4-X-box) protein ligase complex, at least composed of CRBN, CUL4A, DDB1 and RBX1. Interacts directly with DDB1 (By similarity).
Interacts with KCNT1 (By similarity).
Interacts with ILF2 (By similarity).
Interacts with TRAF6 and ECSIT (By similarity).
Interacts with KCNT1 (By similarity).
Interacts with ILF2 (By similarity).
Interacts with TRAF6 and ECSIT (By similarity).
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-48 | Disordered | ||||
Sequence: MAGEGDQQDAAHNMGNHLPLLPADSEDEDDEIEMEVEDQDSKEARKPN | ||||||
Domain | 84-322 | Lon N-terminal | ||||
Sequence: IPVLPEVLMILIPGQTLPLQLSHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQEFGIEVVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQVFPSKPISWEDQYSCKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPENPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCT | ||||||
Domain | 321-429 | CULT | ||||
Sequence: CTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKASNLNLIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTI |
Domain
The CULT domain binds thalidomide and related drugs. Thalidomide binding leads to a change in substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein ligase complex, while no such change is observed in rodents.
Sequence similarities
Belongs to the CRBN family.
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
Q8C7D2-1
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
- Length445
- Mass (Da)50,880
- Last updated2003-03-01 v1
- ChecksumD66C2C3D50366E27
Q8C7D2-2
- Name2
- Differences from canonical
- 1-23: MAGEGDQQDAAHNMGNHLPLLPA → MGNHLPLLP
Q8C7D2-3
- Name3
- Differences from canonical
- 23-23: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A0N4SUK9 | A0A0N4SUK9_MOUSE | Crbn | 253 |
Sequence caution
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_015210 | 1-23 | in isoform 2 | |||
Sequence: MAGEGDQQDAAHNMGNHLPLLPA → MGNHLPLLP | ||||||
Sequence conflict | 10 | in Ref. 3; AAF35895 | ||||
Sequence: A → R | ||||||
Alternative sequence | VSP_039063 | 23 | in isoform 3 | |||
Sequence: Missing | ||||||
Sequence conflict | 48 | in Ref. 3; AAF35895 | ||||
Sequence: N → D | ||||||
Sequence conflict | 71 | in Ref. 1; BAC36214 | ||||
Sequence: H → P | ||||||
Sequence conflict | 82 | in Ref. 3; AAF35895 | ||||
Sequence: Q → R | ||||||
Sequence conflict | 127 | in Ref. 3; AAF35895 | ||||
Sequence: A → G | ||||||
Sequence conflict | 202 | in Ref. 2; AAH86488 | ||||
Sequence: L → V | ||||||
Sequence conflict | 310 | in Ref. 3; AAF35895 | ||||
Sequence: R → A | ||||||
Sequence conflict | 317 | in Ref. 1; BAC36970 | ||||
Sequence: I → V | ||||||
Sequence conflict | 439 | in Ref. 1; BAE35697 | ||||
Sequence: D → N |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AK050557 EMBL· GenBank· DDBJ | BAC34322.1 EMBL· GenBank· DDBJ | mRNA | ||
AK076144 EMBL· GenBank· DDBJ | BAC36214.1 EMBL· GenBank· DDBJ | mRNA | ||
AK077707 EMBL· GenBank· DDBJ | BAC36970.1 EMBL· GenBank· DDBJ | mRNA | ||
AK160219 EMBL· GenBank· DDBJ | BAE35697.1 EMBL· GenBank· DDBJ | mRNA | ||
BC046967 EMBL· GenBank· DDBJ | AAH46967.1 EMBL· GenBank· DDBJ | mRNA | ||
BC069905 EMBL· GenBank· DDBJ | AAH69905.1 EMBL· GenBank· DDBJ | mRNA | ||
BC086488 EMBL· GenBank· DDBJ | AAH86488.1 EMBL· GenBank· DDBJ | mRNA | ||
AF229032 EMBL· GenBank· DDBJ | AAF35895.1 EMBL· GenBank· DDBJ | mRNA | Frameshift |