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UniProtKB - Q8BWG8 (ARRB1_MOUSE)

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Protein

Beta-arrestin-1

Gene

Arrb1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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 keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei250Inositol hexakisphosphateBy similarity1
Binding sitei255Inositol hexakisphosphateBy similarity1
Binding sitei324Inositol hexakisphosphateBy similarity1
Binding sitei326Inositol hexakisphosphateBy similarity1

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionSignal transduction inhibitor
Biological processProtein transport, Transcription, Transcription regulation, Transport

Enzyme and pathway databases

ReactomeiR-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-1
Alternative name(s):
Arrestin beta-1
Gene namesi
Name:Arrb1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:99473 Arrb1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Coated pit, Cytoplasm, Cytoplasmic vesicle, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002051951 – 418Beta-arrestin-1Add BLAST418

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei47PhosphotyrosineCombined sources1
Modified residuei412PhosphoserineCombined sources1

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 conjugation

Proteomic databases

PaxDbiQ8BWG8
PRIDEiQ8BWG8

PTM databases

iPTMnetiQ8BWG8
PhosphoSitePlusiQ8BWG8

Expressioni

Gene expression databases

BgeeiENSMUSG00000018909
CleanExiMM_ARRB1
ExpressionAtlasiQ8BWG8 baseline and differential
GenevisibleiQ8BWG8 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). Interacts with GPR61, GPR62 and GPR135 (By similarity).By similarity1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi224960, 8 interactors
CORUMiQ8BWG8
DIPiDIP-49444N
IntActiQ8BWG8, 17 interactors
MINTiQ8BWG8
STRINGi10090.ENSMUSP00000095866

Structurei

3D structure databases

ProteinModelPortaliQ8BWG8
SMRiQ8BWG8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 163Interaction with SRCBy similarityAdd BLAST163
Regioni45 – 86Interaction with CHRM2By similarityAdd BLAST42
Regioni318 – 418Interaction with TRAF6By similarityAdd BLAST101

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

eggNOGiKOG3865 Eukaryota
ENOG410XR0F LUCA
GeneTreeiENSGT00390000013152
HOGENOMiHOG000231319
HOVERGENiHBG002399
InParanoidiQ8BWG8
KOiK04439
PhylomeDBiQ8BWG8
TreeFamiTF314260

Family and domain databases

Gene3Di2.60.40.640, 1 hit
2.60.40.840, 1 hit
InterProiView 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
PANTHERiPTHR11792 PTHR11792, 1 hit
PfamiView protein in Pfam
PF02752 Arrestin_C, 1 hit
PF00339 Arrestin_N, 1 hit
PRINTSiPR00309 ARRESTIN
SMARTiView protein in SMART
SM01017 Arrestin_C, 1 hit
SUPFAMiSSF81296 SSF81296, 2 hits
PROSITEiView protein in PROSITE
PS00295 ARRESTINS, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative 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.

« Hide

        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
Length:418
Mass (Da):46,973
Last modified:March 1, 2003 - v1
Checksum:i389C24F8CDA06E64
GO
Isoform 1B (identifier: Q8BWG8-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     334-341: Missing.

Show »
Length:410
Mass (Da):46,216
Checksum:i087D1966062C7291
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_019545334 – 341Missing in isoform 1B. 2 Publications8

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
CCDSiCCDS21484.1 [Q8BWG8-2]
CCDS40032.1 [Q8BWG8-1]
RefSeqiNP_796205.1, NM_177231.2 [Q8BWG8-1]
NP_835738.1, NM_178220.3 [Q8BWG8-2]
UniGeneiMm.260193

Genome annotation databases

EnsembliENSMUST00000032995; ENSMUSP00000032995; ENSMUSG00000018909 [Q8BWG8-2]
ENSMUST00000098266; ENSMUSP00000095866; ENSMUSG00000018909 [Q8BWG8-1]
GeneIDi109689
KEGGimmu:109689
UCSCiuc009ilu.1 mouse [Q8BWG8-1]
uc009ilv.1 mouse [Q8BWG8-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiARRB1_MOUSE
AccessioniPrimary (citable) accession number: Q8BWG8
Secondary accession number(s): Q3UH95, Q8BTJ5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 15, 2005
Last sequence update: March 1, 2003
Last modified: June 20, 2018
This is version 130 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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