ID   ARBK1_DIDVI             Reviewed;         689 AA.
AC   O97627;
DT   28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   03-AUG-2022, entry version 112.
DE   RecName: Full=Beta-adrenergic receptor kinase 1;
DE            Short=Beta-ARK-1;
DE            EC=2.7.11.15 {ECO:0000250|UniProtKB:P26817};
DE   AltName: Full=G-protein coupled receptor kinase 2 {ECO:0000250|UniProtKB:P25098};
GN   Name=GRK2 {ECO:0000250|UniProtKB:P25098}; Synonyms=ADRBK1;
OS   Didelphis virginiana (North American opossum) (Didelphis marsupialis
OS   virginiana).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Metatheria; Didelphimorphia; Didelphidae; Didelphis.
OX   NCBI_TaxID=9267;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND MUTAGENESIS OF LYS-220.
RC   TISSUE=Kidney;
RX   PubMed=9892019; DOI=10.1210/mend.13.1.0217;
RA   Lembo P.M.C., Ghahremani M.H., Albert P.R.;
RT   "Receptor selectivity of the cloned opossum G protein-coupled receptor
RT   kinase 2 (GRK2) in intact opossum kidney cells: role in desensitization of
RT   endogenous alpha2C-adrenergic but not serotonin 1B receptors.";
RL   Mol. Endocrinol. 13:138-147(1999).
CC   -!- FUNCTION: Specifically phosphorylates the agonist-occupied form of the
CC       beta-adrenergic and closely related receptors, probably inducing a
CC       desensitization of them (PubMed:9892019). Does not act on HTR1B/5-
CC       hydroxytryptamine 1B receptor (PubMed:9892019). Key regulator of LPAR1
CC       signaling (By similarity). Competes with RALA for binding to LPAR1 thus
CC       affecting the signaling properties of the receptor (By similarity).
CC       Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner
CC       (By similarity). Inhibits relaxation of airway smooth muscle in
CC       response to blue light (By similarity). {ECO:0000250|UniProtKB:P25098,
CC       ECO:0000250|UniProtKB:Q99MK8, ECO:0000269|PubMed:9892019}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-
CC         phosphate + ADP + H(+); Xref=Rhea:RHEA:19429, Rhea:RHEA-COMP:11222,
CC         Rhea:RHEA-COMP:11223, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, ChEBI:CHEBI:456216;
CC         EC=2.7.11.15; Evidence={ECO:0000250|UniProtKB:P26817};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19430;
CC         Evidence={ECO:0000250|UniProtKB:P26817};
CC   -!- ACTIVITY REGULATION: In contrast to other AGC family kinases, the
CC       catalytic activity is solely regulated by the binding of substrates and
CC       ligands, not by phosphorylation of the kinase domain.
CC       {ECO:0000250|UniProtKB:P21146}.
CC   -!- SUBUNIT: Interacts with the heterodimer formed by GNB1 and GNG2 (By
CC       similarity). Interacts with GIT1 (By similarity). Interacts with, and
CC       phosphorylates chemokine-stimulated CCR5 (By similarity). Interacts
CC       with ARRB1 (By similarity). Interacts with LPAR1 and LPAR2 (By
CC       similarity). Interacts with RALA in response to LPAR1 activation (By
CC       similarity). ADRBK1 and RALA mutually inhibit each other's binding to
CC       LPAR1 (By similarity). Interacts with ADRB2 (By similarity).
CC       {ECO:0000250|UniProtKB:P21146, ECO:0000250|UniProtKB:P25098,
CC       ECO:0000250|UniProtKB:P26817}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P26817}. Cell
CC       membrane {ECO:0000250|UniProtKB:P21146}. Postsynapse
CC       {ECO:0000250|UniProtKB:P26817}. Presynapse
CC       {ECO:0000250|UniProtKB:P26817}.
CC   -!- DOMAIN: The PH domain binds anionic phospholipids and helps recruiting
CC       ADRBK1 from the cytoplasm to plasma membrane close to activated
CC       receptors. It mediates binding to G protein beta and gamma subunits,
CC       competing with G-alpha subunits and other G-betagamma effectors.
CC       {ECO:0000250|UniProtKB:P21146}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC       protein kinase family. GPRK subfamily. {ECO:0000305}.
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DR   EMBL; AF087455; AAD11419.1; -; mRNA.
DR   AlphaFoldDB; O97627; -.
DR   SMR; O97627; -.
DR   BRENDA; 2.7.11.15; 9214.
DR   GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR   GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0098794; C:postsynapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0098793; C:presynapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0047696; F:beta-adrenergic receptor kinase activity; IEA:UniProtKB-EC.
DR   GO; GO:0031755; F:Edg-2 lysophosphatidic acid receptor binding; ISS:UniProtKB.
DR   GO; GO:0004703; F:G protein-coupled receptor kinase activity; IEA:InterPro.
DR   GO; GO:1901081; P:negative regulation of relaxation of smooth muscle; ISS:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR   GO; GO:0007165; P:signal transduction; IEA:InterPro.
DR   Gene3D; 1.10.167.10; -; 1.
DR   Gene3D; 2.30.29.30; -; 1.
DR   InterPro; IPR000961; AGC-kinase_C.
DR   InterPro; IPR000239; GPCR_kinase.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR001849; PH_domain.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR016137; RGS.
DR   InterPro; IPR036305; RGS_sf.
DR   InterPro; IPR044926; RGS_subdomain_2.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF00169; PH; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   Pfam; PF00615; RGS; 1.
DR   PRINTS; PR00717; GPCRKINASE.
DR   SMART; SM00233; PH; 1.
DR   SMART; SM00315; RGS; 1.
DR   SMART; SM00133; S_TK_X; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF48097; SSF48097; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR   PROSITE; PS50003; PH_DOMAIN; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   PROSITE; PS50132; RGS; 1.
PE   1: Evidence at protein level;
KW   ATP-binding; Cell membrane; Cell projection; Cytoplasm; Kinase; Membrane;
KW   Nucleotide-binding; Phosphoprotein; Serine/threonine-protein kinase;
KW   Synapse; Transferase.
FT   CHAIN           1..689
FT                   /note="Beta-adrenergic receptor kinase 1"
FT                   /id="PRO_0000260315"
FT   DOMAIN          54..175
FT                   /note="RGS"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00171"
FT   DOMAIN          191..453
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          454..521
FT                   /note="AGC-kinase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT   DOMAIN          558..652
FT                   /note="PH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT   REGION          1..190
FT                   /note="N-terminal"
FT   REGION          665..689
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        317
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         197..205
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         220
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   SITE            3
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   SITE            4
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   SITE            10
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   MOD_RES         670
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   MUTAGEN         220
FT                   /note="K->R: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:9892019"
SQ   SEQUENCE   689 AA;  79783 MW;  8FA39ED496C7D592 CRC64;
     MADLEAVLAD VSYLMAMEKS KATPAARASK KILLPEPSIR SVMQKYLEDR GEVTFEKIFS
     QKLGYLLFRE FCLNHMEEAK PLVEFYDEIK KYEKLDSEEE RTVKSREIFD LYIMKELLSC
     SHLFSKSATE HVQSRLLKKQ VPTDLFQPYI EEICQRFRDD VFQKFIESEK FTRFCQWKNV
     ELNIHLTMND FSVHRIIGRG GFGEVYGCRK ADTGKMYAMK CLDKKRIKMK QGETLALNER
     IMLSLVSTGD CPFIVCMSYA FHTPDKLSFI LDLMNGGDLH YHLSQHGVFS ESDMRFYAAE
     IILGLEHMHS RFVVYRDLKP ANILLDEFGH VRISDLGLAC DFSKKKPHAS VGTHGYMAPE
     VLQKGVAYDS SADWFSLGCM LFKLLRGHSP FRQHKTKDKH EIDRMTLTMA VELPDSFSPE
     LRSLLEGLLQ RDVNRSLGCL GRGAQEVKED PFFKAVDWQM VLLQKYPPPL IPPRGEVNAA
     DAFDIGSFDE EDTKGIKLLD SDQELYRNFP LTISERWQQE VAETVFDTVN SETDRLEARK
     KAKNKQLGHE DDYALGKDCI MHGYMSKMGN PFLTQWQRRY FYLFPNRLEW RAEGEAPQSL
     LTMEEIQSVE ETQIKDRKCI LLKIRGGKQF ILQCDSDPEL VQWKKELRDV YREAQQLLQR
     VPKMKNKPRS PVVELSKMPL TQRGSANGL