P25098 (ARBK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Beta-adrenergic receptor kinase 1
Short name=Beta-ARK-1
EC=2.7.11.15

Alternative name(s):
G-protein coupled receptor kinase 2

Gene names

Name:	ADRBK1
Synonyms:	BARK, BARK1, GRK2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	689 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner. Ref.9
Catalytic activity	ATP + [beta-adrenergic receptor] = ADP + [beta-adrenergic receptor] phosphate.
Subunit structure	Interacts with GIT1 By similarity. Interacts with, and phosphorylates chemokine-stimulated CCR5. Interacts with ARRB1. Interacts with LPAR1 and LPAR2. Interacts with RALA in response to LPAR1 activation. ADRBK1 and RALA mutually inhibit each other's binding to LPAR1. Ref.6 Ref.7 Ref.9
Tissue specificity	Expressed in peripheral blood leukocytes. Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 PH domain. Contains 1 protein kinase domain. Contains 1 RGS domain.

Ontologies

Keywords
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G-protein coupled acetylcholine receptor signaling pathway Inferred from sequence or structural similarity. Source: BHF-UCL activation of phospholipase C activity Traceable author statement. Source: Reactome cardiac muscle contraction Inferred from mutant phenotype PubMed 15051637. Source: BHF-UCL desensitization of G-protein coupled receptor protein signaling pathway Inferred from sequence or structural similarity. Source: BHF-UCL epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome heart development Inferred from electronic annotation. Source: Compara negative regulation of striated muscle contraction Inferred from mutant phenotype PubMed 15051637. Source: BHF-UCL negative regulation of the force of heart contraction by chemical signal Inferred from mutant phenotype PubMed 15051637. Source: BHF-UCL nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome peptidyl-serine phosphorylation Inferred from sequence or structural similarity. Source: BHF-UCL peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of catecholamine secretion Inferred from sequence or structural similarity. Source: BHF-UCL receptor internalization Inferred from direct assay PubMed 20074556. Source: UniProtKB tachykinin receptor signaling pathway Inferred from direct assay PubMed 17986524. Source: BHF-UCL termination of G-protein coupled receptor signaling pathway Inferred from electronic annotation. Source: InterPro
Cellular_component	cytosol Traceable author statement. Source: Reactome plasma membrane Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW Edg-2 lysophosphatidic acid receptor binding Inferred from direct assay Ref.9. Source: UniProtKB G-protein coupled receptor kinase activity Inferred from sequence or structural similarity. Source: BHF-UCL alpha-2A adrenergic receptor binding Inferred from sequence or structural similarity. Source: BHF-UCL beta-adrenergic receptor kinase activity Inferred from electronic annotation. Source: EC phospholipid binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FPR1	P21462	3	EBI-3904795,EBI-2869495

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 689

689

Beta-adrenergic receptor kinase 1

PRO_0000085627

Regions

Domain

54 – 175

122

RGS

Domain

191 – 453

263

Protein kinase

Domain

454 – 521

68

AGC-kinase C-terminal

Domain

558 – 652

95

PH

Nucleotide binding

197 – 205

9

ATP By similarity

Region

1 – 190

190

N-terminal

Sites

Active site

317

1

Proton acceptor By similarity

Binding site

220

1

ATP By similarity

Amino acid modifications

Modified residue

670

1

Phosphoserine Ref.8

Natural variations

Natural variant

184

1

I → T. Ref.12
Corresponds to variant rs55696045 [ dbSNP | Ensembl ].

VAR_040378

Natural variant

578

1

R → Q in a colorectal adenocarcinoma sample; somatic mutation. Ref.12

VAR_040379

Experimental info

Sequence conflict

168 – 185

18

SDKFT…ELNIH → RISSHGFASGRMWSSTST in AAB60689. Ref.3

Sequence conflict

211

1

A → R in CAA43470. Ref.1

Sequence conflict

211

1

A → R in AAB60689. Ref.3

Sequence conflict

422

1

R → H in CAA43470. Ref.1

Sequence conflict

422

1

R → H in AAB60689. Ref.3

Sequence conflict

465

1

K → R in CAA43470. Ref.1

Secondary structure

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689

Helix Strand Turn

Details...

Helix

39 – 49

11

Helix

55 – 59

5

Helix

62 – 75

14

Helix

77 – 79

3

Helix

80 – 93

14

Helix

98 – 109

12

Helix

112 – 118

7

Beta strand

119 – 122

4

Helix

126 – 137

12

Turn

143 – 146

4

Helix

147 – 157

11

Helix

160 – 167

8

Helix

169 – 181

13

Helix

188 – 190

3

Beta strand

191 – 199

9

Beta strand

201 – 210

10

Turn

211 – 213

3

Beta strand

216 – 223

8

Helix

224 – 229

6

Helix

233 – 246

14

Beta strand

247 – 249

3

Beta strand

252 – 254

3

Beta strand

257 – 262

6

Beta strand

264 – 271

8

Helix

279 – 286

8

Helix

291 – 309

19

Turn

310 – 312

3

Helix

320 – 322

3

Beta strand

323 – 325

3

Beta strand

331 – 333

3

Helix

336 – 338

3

Beta strand

343 – 345

3

Helix

354 – 356

3

Helix

359 – 362

4

Helix

371 – 386

16

Helix

393 – 395

3

Helix

399 – 408

10

Beta strand

415 – 417

3

Helix

419 – 428

10

Helix

433 – 435

3

Beta strand

440 – 442

3

Helix

444 – 447

4

Helix

451 – 453

3

Helix

458 – 462

5

Helix

500 – 503

4

Turn

504 – 508

5

Helix

514 – 522

9

Turn

523 – 525

3

Helix

526 – 546

21

Beta strand

555 – 557

3

Beta strand

561 – 568

8

Beta strand

577 – 584

8

Beta strand

587 – 591

5

Beta strand

593 – 596

4

Beta strand

599 – 602

4

Helix

603 – 605

3

Beta strand

606 – 616

11

Beta strand

618 – 624

7

Turn

625 – 627

3

Beta strand

628 – 633

6

Helix

637 – 658

22

Turn

662 – 664

3

Sequences

	Sequence		Length	Mass (Da)
	P25098 [UniParc]. Last modified February 20, 2007. Version 2. Checksum: 4DB68F62841AFA7D	FASTA	689	79,574
	10 20 30 40 50 60 MADLEAVLAD VSYLMAMEKS KATPAARASK KILLPEPSIR SVMQKYLEDR GEVTFEKIFS 70 80 90 100 110 120 QKLGYLLFRD FCLNHLEEAR PLVEFYEEIK KYEKLETEEE RVARSREIFD SYIMKELLAC 130 140 150 160 170 180 SHPFSKSATE HVQGHLGKKQ VPPDLFQPYI EEICQNLRGD VFQKFIESDK FTRFCQWKNV 190 200 210 220 230 240 ELNIHLTMND FSVHRIIGRG GFGEVYGCRK ADTGKMYAMK CLDKKRIKMK QGETLALNER 250 260 270 280 290 300 IMLSLVSTGD CPFIVCMSYA FHTPDKLSFI LDLMNGGDLH YHLSQHGVFS EADMRFYAAE 310 320 330 340 350 360 IILGLEHMHN RFVVYRDLKP ANILLDEHGH VRISDLGLAC DFSKKKPHAS VGTHGYMAPE 370 380 390 400 410 420 VLQKGVAYDS SADWFSLGCM LFKLLRGHSP FRQHKTKDKH EIDRMTLTMA VELPDSFSPE 430 440 450 460 470 480 LRSLLEGLLQ RDVNRRLGCL GRGAQEVKES PFFRSLDWQM VFLQKYPPPL IPPRGEVNAA 490 500 510 520 530 540 DAFDIGSFDE EDTKGIKLLD SDQELYRNFP LTISERWQQE VAETVFDTIN AETDRLEARK 550 560 570 580 590 600 KAKNKQLGHE EDYALGKDCI MHGYMSKMGN PFLTQWQRRY FYLFPNRLEW RGEGEAPQSL 610 620 630 640 650 660 LTMEEIQSVE ETQIKERKCL LLKIRGGKQF ILQCDSDPEL VQWKKELRDA YREAQQLVQR 670 680 VPKMKNKPRS PVVELSKVPL VQRGSANGL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"cDNA cloning and chromosomal localization of the human beta-adrenergic receptor kinase." Benovic J.L., Stone W.C., Huebner K., Croce C., Caron M.G., Lefkowitz R.J. FEBS Lett. 283:122-126(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"High expression of beta-adrenergic receptor kinase in human peripheral blood leukocytes. Isoproterenol and platelet activating factor can induce kinase translocation." Chuang T.T., Sallese M., Ambrosini G., Parruti G., de Blasi A. J. Biol. Chem. 267:6886-6892(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Blood.
[3]	"Structure of the human gene encoding the beta-adrenergic receptor kinase." Penn R.B., Benovic J.L. J. Biol. Chem. 269:14924-14930(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	NHLBI resequencing and genotyping service (RS&G) Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: PNS and Testis.
[6]	"Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2." Aragay A.M., Mellado M., Frade J.M., Martin A.M., Jimenez-Sainz M.C., Martinez-A C., Mayor F. Jr. Proc. Natl. Acad. Sci. U.S.A. 95:2985-2990(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ARRB1.
[7]	"Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus." Oppermann M., Mack M., Proudfoot A.E., Olbrich H. J. Biol. Chem. 274:8875-8885(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CCR5, TISSUE SPECIFICITY.
[8]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-670, MASS SPECTROMETRY. Tissue: Platelet.
[9]	"Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK." Aziziyeh A.I., Li T.T., Pape C., Pampillo M., Chidiac P., Possmayer F., Babwah A.V., Bhattacharya M. Cell. Signal. 21:1207-1217(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH LPAR1; LPAR2 AND RALA.
[10]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"The solution structure and dynamics of the pleckstrin homology domain of G protein-coupled receptor kinase 2 (beta-adrenergic receptor kinase 1). A binding partner of Gbetagamma subunits." Fushman D., Najmabadi-Haske T., Cahill S., Zheng J., Levine H. III, Cowburn D. J. Biol. Chem. 273:2835-2843(1998) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 552-670.
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-184 AND GLN-578.
+	Additional computationally mapped references.

Web resources

Wikipedia

Beta adrenergic receptor kinase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X61157 mRNA. Translation: CAA43470.1.
M80776 mRNA. Translation: AAA58391.1.
U08438 , U08435, U08436, U08437 Genomic DNA. Translation: AAB60689.1.
EU326303 Genomic DNA. Translation: ACA05909.1.
BC037963 mRNA. Translation: AAH37963.1.
BC090863 mRNA. Translation: AAH90863.1.

IPI

IPI00012497.

PIR

A53791.

RefSeq

NP_001610.2. NM_001619.3.

UniGene

Hs.83636.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BAK	NMR	-	A	556-670	[»]
3CIK	X-ray	2.75	A	1-689	[»]
3KRW	X-ray	2.90	A	2-689	[»]
3KRX	X-ray	3.10	A	2-689	[»]
3V5W	X-ray	2.07	A	1-689	[»]

ProteinModelPortal

P25098.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42429N.

IntAct

P25098. 7 interactions.

MINT

MINT-1214643.

STRING

9606.ENSP00000312262.

PTM databases

PhosphoSite

P25098.

Polymorphism databases

DMDM

126302521.

Proteomic databases

PaxDb

P25098.

PRIDE

P25098.

Protocols and materials databases

DNASU

156.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000308595; ENSP00000312262; ENSG00000173020.

GeneID

156.

KEGG

hsa:156.

UCSC

uc009yrn.1. human.

Organism-specific databases

CTD

156.

GeneCards

GC11P067033.

HGNC

HGNC:289. ADRBK1.

HPA

CAB005021.
CAB037248.

MIM

109635. gene.

neXtProt

NX_P25098.

PharmGKB

PA40.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000006742.

HOVERGEN

HBG050559.

InParanoid

P25098.

KO

K00910.

OMA

DFCLKHL.

OrthoDB

EOG4W3SMD.

PhylomeDB

P25098.

Enzyme and pathway databases

BRENDA

2.7.11.15. 2681.

Pathway_Interaction_DB

hdac_classii_pathway. Signaling events mediated by HDAC Class II.
hedgehog_2pathway. Signaling events mediated by the Hedgehog family.
txa2pathway. Thromboxane A2 receptor signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P25098.

Bgee

P25098.

CleanEx

HS_ADRBK1.

Genevestigator

P25098.

GermOnline

ENSG00000173020. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.

InterPro

IPR000961. AGC-kinase_C.
IPR000239. GPCR_kinase.
IPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR000342. Regulat_G_prot_signal.
IPR016137. Regulat_G_prot_signal_superfam.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00169. PH. 1 hit.
PF00069. Pkinase. 1 hit.
PF00615. RGS. 1 hit.
[Graphical view]

PRINTS

PR00717. GPCRKINASE.

SMART

SM00233. PH. 1 hit.
SM00315. RGS. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.
SSF48097. Regulat_G_prot_signal_superfam. 1 hit.

PROSITE

PS51285. AGC_KINASE_CTER. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P25098.

ChEMBL

CHEMBL4079.

ChiTaRS

ADRBK1. human.

DrugBank

DB00171. Adenosine triphosphate.

EvolutionaryTrace

P25098.

GenomeRNAi

156.

NextBio

621.

SOURCE

Search...

Entry information

Entry name

ARBK1_HUMAN

Accession

Primary (citable) accession number: P25098
Secondary accession number(s): B0ZBE1, Q13837, Q6GTT3

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1992
Last sequence update:	February 20, 2007
Last modified:	May 1, 2013
This is version 151 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.