Q8BWG8 · ARRB1_MOUSE
- ProteinBeta-arrestin-1
- GeneArrb1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids418 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as a signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as a signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in IL8-mediated granule release in neutrophils. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity).
Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3 (By similarity).
Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates in the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).
Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3 (By similarity).
Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates in the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 250 | 1D-myo-inositol hexakisphosphate (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 255 | 1D-myo-inositol hexakisphosphate (UniProtKB | ChEBI) | ||||
Sequence: M | ||||||
Binding site | 324 | 1D-myo-inositol hexakisphosphate (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 326 | 1D-myo-inositol hexakisphosphate (UniProtKB | ChEBI) | ||||
Sequence: K |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameBeta-arrestin-1
- Alternative names
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 accessionQ8BWG8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. The monomeric form is predominantly located in the nucleus. The oligomeric form is located in the cytoplasm. Translocates to the nucleus upon stimulation of OPRD1 (By similarity).
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000205195 | 1-418 | Beta-arrestin-1 | |||
Sequence: MGDKGTRVFKKASPNGKLTVYLGKRDFVDHIDLVDPVDGVVLVDPEYLKERRVYVTLTCAFRYGREDLDVLGLTFRKDLFVANVQSFPPAPEDKKPLTRLQERLIKKLGEHACPFTFEIPPNLPCSVTLQPGPEDTGKACGVDYEVKAFCAENLEEKIHKRNSVRLVIRKVQYAPERPGPQPTAETTRQFLMSDKPLHLEASLDKEIYYHGEPISVNVHVTNNTNKTVKKIKISVRQYADICLFNTAQYKCPVAMEEADDNVAPSSTFCKVYTLTPFLANNREKRGLALDGKLKHEDTNLASSTLLREGANREILGIIVSYKVKVKLVVSRGGLLGDLASSDVAVELPFTLMHPKPKEEPPHREVPESETPVDTNLIELDTNDDDIVFEDFARQRLKGMKDDKDEEDDGTGSPHLNNR | ||||||
Modified residue | 47 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 412 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Constitutively phosphorylated at in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and ADRB2 endocytosis but not for ADRB2 binding and desensitization. Once internalized, is rephosphorylated (By similarity).
The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33 (By similarity).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Interaction
Subunit
Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated); phosphorylation of AP2B1 disrupts the interaction. Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CCR2 and GRK2. Interacts with CRR5. Interacts with PTAFR (phosphorylated on serine residues). Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. Interacts with SRC (via the SH3 domain and the protein kinase domain); the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with TACR1. Interacts with RAF1. Interacts with DVL1; the interaction is enhanced by phosphorylation of DVL1. Interacts with DVL2; the interaction is enhanced by phosphorylation of DVL2. Interacts with IGF1R. Interacts with CHUK, IKBKB and MAP3K14. Associates with MAP kinase p38. Part of a MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 (activated). Part of a MAPK signaling complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated). Interacts with GPR143 (By similarity).
Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated) (By similarity).
Interacts with ACKR3 and ACKR4 (By similarity).
Interacts with ARRDC1; the interaction is direct (PubMed:23886940).
Interacts with GPR61, GPR62 and GPR135 (By similarity).
Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated) (By similarity).
Interacts with ACKR3 and ACKR4 (By similarity).
Interacts with ARRDC1; the interaction is direct (PubMed:23886940).
Interacts with GPR61, GPR62 and GPR135 (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q8BWG8 | Card10 P58660 | 4 | EBI-641778, EBI-8344379 | |
BINARY | Q8BWG8 | Dnajb6 O54946 | 6 | EBI-641778, EBI-642500 | |
BINARY | Q8BWG8 | Hax1 O35387 | 6 | EBI-641778, EBI-642449 | |
BINARY | Q8BWG8 | Mdm2 P23804 | 4 | EBI-641778, EBI-641788 | |
BINARY | Q8BWG8 | Nfe2l2 Q60795 | 4 | EBI-641778, EBI-642563 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-163 | Interaction with SRC | ||||
Sequence: MGDKGTRVFKKASPNGKLTVYLGKRDFVDHIDLVDPVDGVVLVDPEYLKERRVYVTLTCAFRYGREDLDVLGLTFRKDLFVANVQSFPPAPEDKKPLTRLQERLIKKLGEHACPFTFEIPPNLPCSVTLQPGPEDTGKACGVDYEVKAFCAENLEEKIHKRNS | ||||||
Region | 45-86 | Interaction with CHRM2 | ||||
Sequence: PEYLKERRVYVTLTCAFRYGREDLDVLGLTFRKDLFVANVQS | ||||||
Region | 318-418 | Interaction with TRAF6 | ||||
Sequence: IVSYKVKVKLVVSRGGLLGDLASSDVAVELPFTLMHPKPKEEPPHREVPESETPVDTNLIELDTNDDDIVFEDFARQRLKGMKDDKDEEDDGTGSPHLNNR | ||||||
Compositional bias | 353-369 | Basic and acidic residues | ||||
Sequence: HPKPKEEPPHREVPESE | ||||||
Region | 353-375 | Disordered | ||||
Sequence: HPKPKEEPPHREVPESETPVDTN | ||||||
Compositional bias | 397-412 | Basic and acidic residues | ||||
Sequence: KGMKDDKDEEDDGTGS | ||||||
Region | 397-418 | Disordered | ||||
Sequence: KGMKDDKDEEDDGTGSPHLNNR |
Domain
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1. Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface (By similarity).
The N-terminus binds InsP6 with low affinity.
The C-terminus binds InsP6 with high affinity.
Sequence similarities
Belongs to the arrestin family.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q8BWG8-1
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.
- Name1A
- Length418
- Mass (Da)46,973
- Last updated2003-03-01 v1
- Checksum389C24F8CDA06E64
Q8BWG8-2
- Name1B
- Differences from canonical
- 334-341: Missing
Computationally mapped potential isoform sequences
There are 4 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_019545 | 334-341 | in isoform 1B | |||
Sequence: Missing | ||||||
Compositional bias | 353-369 | Basic and acidic residues | ||||
Sequence: HPKPKEEPPHREVPESE | ||||||
Compositional bias | 397-412 | Basic and acidic residues | ||||
Sequence: KGMKDDKDEEDDGTGS |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AK052588 EMBL· GenBank· DDBJ | BAC35050.1 EMBL· GenBank· DDBJ | mRNA | ||
AK090090 EMBL· GenBank· DDBJ | BAC41087.1 EMBL· GenBank· DDBJ | mRNA | ||
AK144054 EMBL· GenBank· DDBJ | BAE25673.1 EMBL· GenBank· DDBJ | mRNA | ||
AK147508 EMBL· GenBank· DDBJ | BAE27962.1 EMBL· GenBank· DDBJ | mRNA | ||
AK165514 EMBL· GenBank· DDBJ | BAE38230.1 EMBL· GenBank· DDBJ | mRNA | ||
BC108969 EMBL· GenBank· DDBJ | AAI08970.1 EMBL· GenBank· DDBJ | mRNA | ||
BC108970 EMBL· GenBank· DDBJ | AAI08971.1 EMBL· GenBank· DDBJ | mRNA |