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Protein

Beta-arrestin-1

Gene

ARRB1

Organism
Homo sapiens (Human)
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. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils. 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. 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 similarity19 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

  • alpha-1A adrenergic receptor binding Source: Ensembl
  • alpha-1B adrenergic receptor binding Source: Ensembl
  • angiotensin receptor binding Source: UniProtKB
  • AP-2 adaptor complex binding Source: Ensembl
  • arrestin family protein binding Source: UniProtKB
  • clathrin adaptor activity Source: Ensembl
  • cysteine-type endopeptidase inhibitor activity involved in apoptotic process Source: Ensembl
  • enzyme inhibitor activity Source: ProtInc
  • estrogen receptor binding Source: Ensembl
  • follicle-stimulating hormone receptor binding Source: Ensembl
  • GTPase activator activity Source: UniProtKB
  • insulin-like growth factor receptor binding Source: UniProtKB
  • ion channel binding Source: Ensembl
  • mitogen-activated protein kinase kinase binding Source: Ensembl
  • protein phosphorylated amino acid binding Source: Ensembl
  • transcription factor binding Source: UniProtKB
  • transcription regulatory region DNA binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: UniProtKB
  • 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: UniProtKB
  • G-protein coupled receptor signaling pathway Source: Reactome
  • membrane organization Source: Reactome
  • negative regulation of ERK1 and ERK2 cascade Source: Ensembl
  • negative regulation of GTPase activity Source: Ensembl
  • negative regulation of interleukin-6 production Source: UniProtKB
  • negative regulation of interleukin-8 production Source: UniProtKB
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • negative regulation of Notch signaling pathway Source: UniProtKB
  • negative regulation of protein ubiquitination Source: UniProtKB
  • phototransduction Source: Ensembl
  • platelet activation Source: Reactome
  • 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: BHF-UCL
  • positive regulation of histone H4 acetylation Source: UniProtKB
  • positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
  • positive regulation of peptidyl-serine phosphorylation Source: Ensembl
  • positive regulation of protein binding Source: Ensembl
  • 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: UniProtKB
  • positive regulation of smooth muscle cell apoptotic process Source: Ensembl
  • positive regulation of transcription by RNA polymerase II Source: BHF-UCL
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein transport Source: UniProtKB-KW
  • protein ubiquitination Source: UniProtKB
  • response to drug Source: Ensembl
  • stress fiber assembly Source: UniProtKB
  • transcription by RNA polymerase II Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-418555 G alpha (s) signalling events
R-HSA-432720 Lysosome Vesicle Biogenesis
R-HSA-432722 Golgi Associated Vesicle Biogenesis
R-HSA-456926 Thrombin signalling through proteinase activated receptors (PARs)
R-HSA-5635838 Activation of SMO
R-HSA-5674135 MAP2K and MAPK activation
R-HSA-5689880 Ub-specific processing proteases
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802952 Signaling by BRAF and RAF fusions
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828 Clathrin-mediated endocytosis
SignaLinkiP49407
SIGNORiP49407

Protein family/group databases

MoonProtiP49407

Names & Taxonomyi

Protein namesi
Recommended name:
Beta-arrestin-1
Alternative name(s):
Arrestin beta-1
Non-visual arrestin-21 Publication
Gene namesi
Name:ARRB1
Synonyms:ARR1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000137486.16
HGNCiHGNC:711 ARRB1
MIMi107940 gene
neXtProtiNX_P49407

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

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi169R → E: Constitutive active; enables phosphorylation-independent binding to GPCRs. 1 Publication1
Mutagenesisi388F → A: Abolishes interaction with AP2B1. 1 Publication1
Mutagenesisi390D → P: Abolishes interaction with AP2B1. 1 Publication1
Mutagenesisi393R → A: Abolishes interaction with AP2B1. 1 Publication1

Organism-specific databases

DisGeNETi408
OpenTargetsiENSG00000137486
PharmGKBiPA59

Chemistry databases

ChEMBLiCHEMBL1795088

Polymorphism and mutation databases

BioMutaiARRB1
DMDMi20141238

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002051941 – 418Beta-arrestin-1Add BLAST418

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei47PhosphotyrosineBy similarity1
Modified residuei412Phosphoserine; by GRK5Combined sources1 Publication1

Post-translational modificationi

Constitutively phosphorylated at Ser-412 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.1 Publication
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 USP33.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP49407
MaxQBiP49407
PaxDbiP49407
PeptideAtlasiP49407
PRIDEiP49407

2D gel databases

OGPiP49407

PTM databases

iPTMnetiP49407
PhosphoSitePlusiP49407

Expressioni

Gene expression databases

BgeeiENSG00000137486
CleanExiHS_ARRB1
ExpressionAtlasiP49407 baseline and differential
GenevisibleiP49407 HS

Organism-specific databases

HPAiCAB003763
HPA049318

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 GPR143. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated at 'Tyr-737'); phosphorylation of AP2B1 at 'Tyr-737' 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 CHUK, IKBKB and MAP3K14. 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. 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) (By similarity). Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4. Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538).By similarity19 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi106901, 259 interactors
DIPiDIP-29979N
ELMiP49407
IntActiP49407, 230 interactors
MINTiP49407
STRINGi9606.ENSP00000409581

Chemistry databases

BindingDBiP49407

Structurei

Secondary structure

1418
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi384 – 394Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2IV8X-ray2.80P/Q383-402[»]
ProteinModelPortaliP49407
SMRiP49407
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49407

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 163Interaction with SRCBy similarityAdd BLAST163
Regioni45 – 86Interaction with CHRM2By similarityAdd BLAST42
Regioni318 – 418Interaction with TRAF61 PublicationAdd BLAST101

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi385 – 395[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motifAdd BLAST11

Domaini

The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1 (By similarity). 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.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
InParanoidiP49407
KOiK04439
OMAiYCPASVS
OrthoDBiEOG091G05M2
PhylomeDBiP49407
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: P49407-1) [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 HAYPFTFEIP 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 TVAPSSTFCK VYTLTPFLAN NREKRGLALD GKLKHEDTNL
310 320 330 340 350
ASSTLLREGA NREILGIIVS YKVKVKLVVS RGGLLGDLAS SDVAVELPFT
360 370 380 390 400
LMHPKPKEEP PHREVPENET PVDTNLIELD TNDDDIVFED FARQRLKGMK
410
DDKEEEEDGT GSPQLNNR
Length:418
Mass (Da):47,066
Last modified:March 5, 2002 - v2
Checksum:i0A3C135092338D10
GO
Isoform 1B (identifier: P49407-2) [UniParc]FASTAAdd to basket

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

Show »
Length:410
Mass (Da):46,309
Checksum:i4FBA2B09E6C2D236
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti146V → A in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti146V → A in AAA35558 (PubMed:8486659).Curated1
Sequence conflicti165R → G in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti165R → G in AAA35558 (PubMed:8486659).Curated1
Sequence conflicti229K → E in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti229K → E in AAA35558 (PubMed:8486659).Curated1
Sequence conflicti329V → E in AAC33295 (Ref. 2) Curated1
Sequence conflicti329V → E in AAC34123 (Ref. 2) Curated1
Sequence conflicti400K → E in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti400K → E in AAA35558 (PubMed:8486659).Curated1
Sequence conflicti414Q → R in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti414Q → R in AAA35558 (PubMed:8486659).Curated1
Sequence conflicti417N → D in AAA35559 (PubMed:8486659).Curated1
Sequence conflicti417N → D in AAA35558 (PubMed:8486659).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_000322334 – 341Missing in isoform 1B. 3 Publications8

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L04685 mRNA Translation: AAA35559.1
L04685 mRNA Translation: AAA35558.1
AF084040 mRNA Translation: AAC33295.1
AF084940 mRNA Translation: AAC34123.1
DQ314865 Genomic DNA Translation: ABC40724.1
FJ348262 mRNA Translation: ACI96306.1
CH471076 Genomic DNA Translation: EAW74962.1
BC003636 mRNA Translation: AAH03636.1
CCDSiCCDS31640.1 [P49407-2]
CCDS44684.1 [P49407-1]
PIRiB46682
RefSeqiNP_004032.2, NM_004041.4 [P49407-1]
NP_064647.1, NM_020251.3 [P49407-2]
UniGeneiHs.503284
Hs.625320

Genome annotation databases

EnsembliENST00000360025; ENSP00000353124; ENSG00000137486 [P49407-2]
ENST00000420843; ENSP00000409581; ENSG00000137486 [P49407-1]
GeneIDi408
KEGGihsa:408
UCSCiuc001owe.3 human [P49407-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiARRB1_HUMAN
AccessioniPrimary (citable) accession number: P49407
Secondary accession number(s): B6V9G8
, O75625, O75630, Q2PP20, Q9BTK8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: March 5, 2002
Last modified: April 25, 2018
This is version 176 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health