UniProtKB - Q8BWG8 (ARRB1_MOUSE)
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Protein
Beta-arrestin-1
Gene
Arrb1
Organism
Mus musculus (Mouse)
Status
Functioni
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 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 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 to the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).By similarity3 Publications
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 250 | Inositol hexakisphosphateBy similarity | 1 | |
Binding sitei | 255 | Inositol hexakisphosphateBy similarity | 1 | |
Binding sitei | 324 | Inositol hexakisphosphateBy similarity | 1 | |
Binding sitei | 326 | Inositol hexakisphosphateBy similarity | 1 |
GO - Molecular functioni
- alpha-1A adrenergic receptor binding Source: Ensembl
- alpha-1B adrenergic receptor binding Source: Ensembl
- angiotensin receptor binding Source: MGI
- AP-2 adaptor complex binding Source: Ensembl
- arrestin family protein binding Source: MGI
- clathrin adaptor activity Source: Ensembl
- cysteine-type endopeptidase inhibitor activity involved in apoptotic process Source: UniProtKB
- estrogen receptor binding Source: Ensembl
- follicle-stimulating hormone receptor binding Source: Ensembl
- GTPase activator activity Source: MGI
- insulin-like growth factor receptor binding Source: MGI
- ion channel binding Source: Ensembl
- mitogen-activated protein kinase kinase binding Source: UniProtKB
- protein phosphorylated amino acid binding Source: Ensembl
- transcription factor binding Source: MGI
- transcription regulatory region DNA binding Source: MGI
- ubiquitin protein ligase binding Source: MGI
- V2 vasopressin receptor binding Source: Ensembl
GO - Biological processi
- activation of MAPK activity Source: Ensembl
- follicle-stimulating hormone signaling pathway Source: Ensembl
- G-protein coupled receptor internalization Source: MGI
- negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
- negative regulation of ERK1 and ERK2 cascade Source: Ensembl
- negative regulation of GTPase activity Source: Ensembl
- negative regulation of interleukin-6 production Source: MGI
- negative regulation of interleukin-8 production Source: MGI
- negative regulation of NF-kappaB transcription factor activity Source: MGI
- negative regulation of Notch signaling pathway Source: UniProtKB
- negative regulation of protein ubiquitination Source: MGI
- phototransduction Source: MGI
- positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: Ensembl
- positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
- positive regulation of histone acetylation Source: MGI
- positive regulation of histone H4 acetylation Source: MGI
- positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: UniProtKB
- positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
- positive regulation of protein binding Source: UniProtKB
- positive regulation of protein phosphorylation Source: UniProtKB
- positive regulation of protein ubiquitination Source: Ensembl
- positive regulation of receptor internalization Source: UniProtKB
- positive regulation of Rho protein signal transduction Source: MGI
- positive regulation of smooth muscle cell apoptotic process Source: Ensembl
- positive regulation of transcription by RNA polymerase II Source: MGI
- proteasome-mediated ubiquitin-dependent protein catabolic process Source: MGI
- protein transport Source: UniProtKB-KW
- protein ubiquitination Source: MGI
- regulation of apoptotic process Source: UniProtKB
- regulation of G-protein coupled receptor protein signaling pathway Source: MGI
- response to drug Source: Ensembl
- stress fiber assembly Source: MGI
- transcription by RNA polymerase II Source: MGI
- ubiquitin-dependent protein catabolic process Source: UniProtKB
Keywordsi
Molecular function | Signal transduction inhibitor |
Biological process | Protein transport, Transcription, Transcription regulation, Transport |
Enzyme and pathway databases
Reactomei | R-MMU-418555. G alpha (s) signalling events. R-MMU-432720. Lysosome Vesicle Biogenesis. R-MMU-432722. Golgi Associated Vesicle Biogenesis. R-MMU-456926. Thrombin signalling through proteinase activated receptors (PARs). R-MMU-5635838. Activation of SMO. R-MMU-5674135. MAP2K and MAPK activation. R-MMU-5689880. Ub-specific processing proteases. R-MMU-8856825. Cargo recognition for clathrin-mediated endocytosis. R-MMU-8856828. Clathrin-mediated endocytosis. |
Names & Taxonomyi
Protein namesi | Recommended name: Beta-arrestin-1Alternative name(s): Arrestin beta-1 |
Gene namesi | Name:Arrb1 |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:99473. Arrb1. |
Subcellular locationi
Keywords - Cellular componenti
Cell membrane, Cell projection, Coated pit, Cytoplasm, Cytoplasmic vesicle, Membrane, NucleusPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000205195 | 1 – 418 | Beta-arrestin-1Add BLAST | 418 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 47 | PhosphotyrosineCombined sources | 1 | |
Modified residuei | 412 | PhosphoserineCombined sources | 1 |
Post-translational modificationi
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).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).By similarity
Keywords - PTMi
Phosphoprotein, Ubl conjugationProteomic databases
PaxDbi | Q8BWG8. |
PRIDEi | Q8BWG8. |
PTM databases
iPTMneti | Q8BWG8. |
PhosphoSitePlusi | Q8BWG8. |
Expressioni
Gene expression databases
Bgeei | ENSMUSG00000018909. |
CleanExi | MM_ARRB1. |
ExpressionAtlasi | Q8BWG8. baseline and differential. |
Genevisiblei | Q8BWG8. MM. |
Interactioni
Subunit structurei
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).By similarity1 Publication
Binary interactionsi
GO - Molecular functioni
- alpha-1A adrenergic receptor binding Source: Ensembl
- alpha-1B adrenergic receptor binding Source: Ensembl
- angiotensin receptor binding Source: MGI
- AP-2 adaptor complex binding Source: Ensembl
- arrestin family protein binding Source: MGI
- clathrin adaptor activity Source: Ensembl
- estrogen receptor binding Source: Ensembl
- follicle-stimulating hormone receptor binding Source: Ensembl
- insulin-like growth factor receptor binding Source: MGI
- ion channel binding Source: Ensembl
- mitogen-activated protein kinase kinase binding Source: UniProtKB
- protein phosphorylated amino acid binding Source: Ensembl
- transcription factor binding Source: MGI
- ubiquitin protein ligase binding Source: MGI
- V2 vasopressin receptor binding Source: Ensembl
Protein-protein interaction databases
BioGridi | 224960. 8 interactors. |
CORUMi | Q8BWG8. |
DIPi | DIP-49444N. |
IntActi | Q8BWG8. 17 interactors. |
MINTi | Q8BWG8. |
STRINGi | 10090.ENSMUSP00000095866. |
Structurei
3D structure databases
ProteinModelPortali | Q8BWG8. |
SMRi | Q8BWG8. |
ModBasei | Search... |
MobiDBi | Search... |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 163 | Interaction with SRCBy similarityAdd BLAST | 163 | |
Regioni | 45 – 86 | Interaction with CHRM2By similarityAdd BLAST | 42 | |
Regioni | 318 – 418 | Interaction with TRAF6By similarityAdd BLAST | 101 |
Domaini
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).By similarity
The N-terminus binds InsP6 with low affinity.By similarity
The C-terminus binds InsP6 with high affinity.By similarity
Sequence similaritiesi
Belongs to the arrestin family.Curated
Phylogenomic databases
eggNOGi | KOG3865. Eukaryota. ENOG410XR0F. LUCA. |
GeneTreei | ENSGT00390000013152. |
HOGENOMi | HOG000231319. |
HOVERGENi | HBG002399. |
InParanoidi | Q8BWG8. |
KOi | K04439. |
PhylomeDBi | Q8BWG8. |
TreeFami | TF314260. |
Family and domain databases
Gene3Di | 2.60.40.640. 1 hit. 2.60.40.840. 1 hit. |
InterProi | View protein in InterPro IPR000698. Arrestin. IPR011021. Arrestin-like_N. IPR014752. Arrestin_C. IPR011022. Arrestin_C-like. IPR017864. Arrestin_CS. IPR014753. Arrestin_N. IPR014756. Ig_E-set. |
PANTHERi | PTHR11792. PTHR11792. 1 hit. |
Pfami | View protein in Pfam PF02752. Arrestin_C. 1 hit. PF00339. Arrestin_N. 1 hit. |
PRINTSi | PR00309. ARRESTIN. |
SMARTi | View protein in SMART SM01017. Arrestin_C. 1 hit. |
SUPFAMi | SSF81296. SSF81296. 2 hits. |
PROSITEi | View protein in PROSITE PS00295. ARRESTINS. 1 hit. |
s (2)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basket
Isoform 1A (identifier: Q8BWG8-1) [UniParc]FASTAAdd to basket
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.
10 20 30 40 50
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE
60 70 80 90 100
RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPPA PEDKKPLTRL
110 120 130 140 150
QERLIKKLGE HACPFTFEIP PNLPCSVTLQ PGPEDTGKAC GVDYEVKAFC
160 170 180 190 200
AENLEEKIHK RNSVRLVIRK VQYAPERPGP QPTAETTRQF LMSDKPLHLE
210 220 230 240 250
ASLDKEIYYH GEPISVNVHV TNNTNKTVKK IKISVRQYAD ICLFNTAQYK
260 270 280 290 300
CPVAMEEADD NVAPSSTFCK VYTLTPFLAN NREKRGLALD GKLKHEDTNL
310 320 330 340 350
ASSTLLREGA NREILGIIVS YKVKVKLVVS RGGLLGDLAS SDVAVELPFT
360 370 380 390 400
LMHPKPKEEP PHREVPESET PVDTNLIELD TNDDDIVFED FARQRLKGMK
410
DDKDEEDDGT GSPHLNNR
Isoform 1B (identifier: Q8BWG8-2) [UniParc]FASTAAdd to basket
The sequence of this isoform differs from the canonical sequence as follows:
334-341: Missing.
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_019545 | 334 – 341 | Missing in isoform 1B. 2 Publications | 8 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AK052588 mRNA. Translation: BAC35050.1. AK090090 mRNA. Translation: BAC41087.1. AK144054 mRNA. Translation: BAE25673.1. AK147508 mRNA. Translation: BAE27962.1. AK165514 mRNA. Translation: BAE38230.1. BC108969 mRNA. Translation: AAI08970.1. BC108970 mRNA. Translation: AAI08971.1. |
CCDSi | CCDS21484.1. [Q8BWG8-2] CCDS40032.1. [Q8BWG8-1] |
RefSeqi | NP_796205.1. NM_177231.2. [Q8BWG8-1] NP_835738.1. NM_178220.3. [Q8BWG8-2] |
UniGenei | Mm.260193. |
Genome annotation databases
Ensembli | ENSMUST00000032995; ENSMUSP00000032995; ENSMUSG00000018909. [Q8BWG8-2] ENSMUST00000098266; ENSMUSP00000095866; ENSMUSG00000018909. [Q8BWG8-1] |
GeneIDi | 109689. |
KEGGi | mmu:109689. |
UCSCi | uc009ilu.1. mouse. [Q8BWG8-1] uc009ilv.1. mouse. [Q8BWG8-2] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Entry informationi
Entry namei | ARRB1_MOUSE | |
Accessioni | Q8BWG8Primary (citable) accession number: Q8BWG8 Secondary accession number(s): Q3UH95, Q8BTJ5 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | February 15, 2005 |
Last sequence update: | March 1, 2003 | |
Last modified: | March 28, 2018 | |
This is version 127 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |