Target Information
Target General Information | Top | |||||
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Target ID |
T41646
(Former ID: TTDI00183)
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Target Name |
Beta-arrestin-1 (ARRB1)
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Synonyms |
Non-visual arrestin-2; Betaarrestin1; Arrestin beta1; Arrestin beta-1; ARR1
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Gene Name |
ARRB1
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Target Type |
Literature-reported target
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[1] | ||||
Function |
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). 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. Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes.
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BioChemical Class |
Arrestin protein
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UniProt ID | ||||||
Sequence |
MGDKGTRVFKKASPNGKLTVYLGKRDFVDHIDLVDPVDGVVLVDPEYLKERRVYVTLTCA
FRYGREDLDVLGLTFRKDLFVANVQSFPPAPEDKKPLTRLQERLIKKLGEHAYPFTFEIP PNLPCSVTLQPGPEDTGKACGVDYEVKAFCAENLEEKIHKRNSVRLVIRKVQYAPERPGP QPTAETTRQFLMSDKPLHLEASLDKEIYYHGEPISVNVHVTNNTNKTVKKIKISVRQYAD ICLFNTAQYKCPVAMEEADDTVAPSSTFCKVYTLTPFLANNREKRGLALDGKLKHEDTNL ASSTLLREGANREILGIIVSYKVKVKLVVSRGGLLGDLASSDVAVELPFTLMHPKPKEEP PHREVPENETPVDTNLIELDTNDDDIVFEDFARQRLKGMKDDKEEEEDGTGSPQLNNR Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T88ENR |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
Structure Description | Phosphorylated turkey beta1 adrenoceptor with bound agonist formoterol coupled to arrestin-2 in lipid nanodisc. | PDB:6TKO | ||||
Method | Electron microscopy | Resolution | 3.30 Å | Mutation | Yes | [2] |
PDB Sequence |
TRVFKKASPN
15 GKLTVYLGKR25 DFVDHIDLVD35 PVDGVVLVDP45 EYLKERRVYV55 TLTCAFRYGR 65 EDCDVLGLTF75 RKDLFVANVQ85 SFPPAPEDKK95 PLTRLQERLI105 KKLGEHAYPF 115 TFEIPPNLPC125 SVTLQPGPED135 TGKACGVDYE145 VKAFCAENLE155 EKIHKRNSVR 165 LVIEKVQYAP175 ERPGPQPTAE185 TTRQFLMSDK195 PLHLEASLDK205 EIYYHGEPIS 215 VNVHVTNNTN225 KTVKKIKISV235 RQYADICLFN245 TAQYKCPVAM255 EEADDTVAPS 265 STFCKVYTLT275 PFLANNREKR285 GLALDGKLKH295 EDTNLASSTL305 LREGANREIL 315 GIIVSYKVKV325 KLVVSSDVAV345 ELPFTLMHPK355 PKEE
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: Phosphonothreonine | Ligand Info | |||||
Structure Description | Phosphorylated turkey beta1 adrenoceptor with bound agonist formoterol coupled to arrestin-2 in lipid nanodisc. | PDB:6TKO | ||||
Method | Electron microscopy | Resolution | 3.30 Å | Mutation | Yes | [2] |
PDB Sequence |
TRVFKKASPN
15 GKLTVYLGKR25 DFVDHIDLVD35 PVDGVVLVDP45 EYLKERRVYV55 TLTCAFRYGR 65 EDCDVLGLTF75 RKDLFVANVQ85 SFPPAPEDKK95 PLTRLQERLI105 KKLGEHAYPF 115 TFEIPPNLPC125 SVTLQPGPED135 TGKACGVDYE145 VKAFCAENLE155 EKIHKRNSVR 165 LVIEKVQYAP175 ERPGPQPTAE185 TTRQFLMSDK195 PLHLEASLDK205 EIYYHGEPIS 215 VNVHVTNNTN225 KTVKKIKISV235 RQYADICLFN245 TAQYKCPVAM255 EEADDTVAPS 265 STFCKVYTLT275 PFLANNREKR285 GLALDGKLKH295 EDTNLASSTL305 LREGANREIL 315 GIIVSYKVKV325 KLVVSSDVAV345 ELPFTLMHPK355 PKEE
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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MAPK signaling pathway | hsa04010 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Chemokine signaling pathway | hsa04062 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Endocytosis | hsa04144 | Affiliated Target |
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Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
Hedgehog signaling pathway | hsa04340 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Dopaminergic synapse | hsa04728 | Affiliated Target |
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Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
Olfactory transduction | hsa04740 | Affiliated Target |
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Class: Organismal Systems => Sensory system | Pathway Hierarchy | ||
Relaxin signaling pathway | hsa04926 | Affiliated Target |
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Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
Parathyroid hormone synthesis, secretion and action | hsa04928 | Affiliated Target |
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Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
GnRH secretion | hsa04929 | Affiliated Target |
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Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
Click to Show/Hide the Information of Affiliated Human Pathways |
Degree | 31 | Degree centrality | 3.33E-03 | Betweenness centrality | 5.45E-03 |
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Closeness centrality | 2.56E-01 | Radiality | 1.44E+01 | Clustering coefficient | 8.39E-02 |
Neighborhood connectivity | 3.36E+01 | Topological coefficient | 4.94E-02 | Eccentricity | 11 |
Download | Click to Download the Full PPI Network of This Target | ||||
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
References | Top | |||||
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REF 1 | Beta-Arrestin1 Levels in Mononuclear Leukocytes Support Depression Scores for Women with Premenstrual Dysphoric Disorder. Int J Environ Res Public Health. 2015 Dec 22;13(1):ijerph13010043. | |||||
REF 2 | Molecular basis of Beta-arrestin coupling to formoterol-bound Beta(1)-adrenoceptor. Nature. 2020 Jul;583(7818):862-866. |
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