Q62833 (GRK5_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
G protein-coupled receptor kinase 5
EC=2.7.11.16

Alternative name(s):
G protein-coupled receptor kinase GRK5

Gene names

Name:	Grk5
Synonyms:	Gprk5

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	590 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor By similarity. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro) By similarity. Ref.2
Catalytic activity	ATP + [G-protein-coupled receptor] = ADP + [G-protein-coupled receptor] phosphate.
Enzyme regulation	Inhibited by calmodulin with an IC50 of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid By similarity.
Subunit structure	Interacts with ST13 (via the C-terminus 303-319 AA) By similarity. Interacts with TP53/p53 By similarity. Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) By similarity. Interacts with HDAC5 By similarity.
Subcellular location	Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein By similarity. Note: Predominantly localized at the plasma membrane, targeted to the cell surface through the interaction with phospholipids. Nucleus localization is regulated in a GPCR and Ca2+/calmodulin-dependent fashion By similarity. Ref.5
Tissue specificity	Not expressed ubiquitously in brain but is mainly localize in limbic brain regions with a very prominent expression in the lateral septal area. Ref.4
Induction	By cocaine in the lateral septum. Up-regulated in the failing heart. Ref.3 Ref.4
Post-translational modification	Autophosphorylated By similarity. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity By similarity.
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 protein kinase domain. Contains 1 RGS domain.

Ontologies

Keywords
Biological process	Apoptosis Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Ligand	ATP-binding Lipid-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW desensitization of G-protein coupled receptor protein signaling pathway Inferred from mutant phenotype Ref.1. Source: RGD negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB response to drug Inferred from expression pattern PubMed 12384166. Source: RGD termination of G-protein coupled receptor signaling pathway Inferred from electronic annotation. Source: InterPro
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW G-protein coupled receptor kinase activity Inferred by curator Ref.1. Source: RGD lipid binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 590	590	G protein-coupled receptor kinase 5		PRO_0000085973
Regions
	Domain	53 – 171	119	RGS
	Domain	186 – 448	263	Protein kinase
	Domain	449 – 514	66	AGC-kinase C-terminal
	Nucleotide binding	192 – 200	9	ATP By similarity
	Region	1 – 185	185	N-terminal
	Region	20 – 39	20	Interaction with calmodulin By similarity
	Region	546 – 565	20	Sufficient for membrane localization By similarity
	Motif	388 – 395	8	Nuclear localization signal By similarity
Sites
	Active site	311	1	Proton acceptor By similarity
	Binding site	215	1	ATP By similarity
Amino acid modifications
	Modified residue	484	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	485	1	Phosphothreonine; by autocatalysis By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q62833 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: DCAE0C00B1247AFA	FASTA	590	67,783
	10 20 30 40 50 60 MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIN QCEDLRRTID RDYYSLCDKQ 70 80 90 100 110 120 PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA KGKEIMTKYL SPKSPVFIAQ 130 140 150 160 170 180 VGQDLVSQTE KKLLQSPCKE LFSACAQSVH DYLKGDPFHE YLDSMYFDRF LQWKWLERQP 190 200 210 220 230 240 VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK 250 260 270 280 290 300 VNSQFVVNLA YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE 310 320 330 340 350 360 DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG YMAPEVLNNQ 370 380 390 400 410 420 RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR VLETEEVYSP KFSEEAKSIC 430 440 450 460 470 480 NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI 490 500 510 520 530 540 EQFSTVKGVN LDHTDDDFYS KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS 550 560 570 580 590 QPPEPPKKGL FHRLFRRQHQ NNSKSSPTPK TSCNHRINSN HINSNSTGSS

References

[1]	"Involvement of G protein-coupled receptor kinase 5 in homologous desensitization of the thyrotropin receptor." Nagayama Y., Tanaka K., Hara T., Namba H., Yamashita S., Taniyama K., Niwa M. J. Biol. Chem. 271:10143-10148(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Differential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases." Tiberi M., Nash S.R., Bertrand L., Lefkowitz R.J., Caron M.G. J. Biol. Chem. 271:3771-3778(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[3]	"Myocardial distribution and regulation of GRK and beta-arrestin isoforms in congestive heart failure in rats." Vinge L.E., Oie E., Andersson Y., Grogaard H.K., Andersen G., Attramadal H. Am. J. Physiol. 281:H2490-H2499(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[4]	"Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain." Erdtmann-Vourliotis M., Mayer P., Ammon S., Riechert U., Hollt V. Brain Res. Mol. Brain Res. 95:129-137(2001) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, INDUCTION.
[5]	"Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-prone rats." Yi X.P., Gerdes A.M., Li F. Hypertension 39:1058-1063(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U34841 mRNA. Translation: AAC52536.1.
IPI	IPI00230806.
RefSeq	NP_110456.1. NM_030829.1.
UniGene	Rn.6500.
3D structure databases
ProteinModelPortal	Q62833.
SMR	Q62833. Positions 23-532.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000015687.
PTM databases
PhosphoSite	Q62833.
Proteomic databases
PaxDb	Q62833.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	59075.
KEGG	rno:59075.
Organism-specific databases
CTD	2869.
RGD	61985. Grk5.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000006742.
HOVERGEN	HBG004532.
InParanoid	Q62833.
KO	K08291.
OrthoDB	EOG4HHP24.
Enzyme and pathway databases
BRENDA	2.7.11.16. 5301.
Gene expression databases
ArrayExpress	Q62833.
Genevestigator	Q62833.
GermOnline	ENSRNOG00000011439. Rattus norvegicus.
Family and domain databases
InterPro	IPR000961. AGC-kinase_C. IPR000239. GPCR_kinase. IPR011009. Kinase-like_dom. 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. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. PF00615. RGS. 1 hit. [Graphical view]
PRINTS	PR00717. GPCRKINASE.
SMART	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. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. False negative. PS50132. RGS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	611692.

Entry information

Entry name

GRK5_RAT

Accession

Primary (citable) accession number: Q62833

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	April 3, 2013
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program