Q8VEB1 (GRK5_MOUSE) 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

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [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 › Mus › Mus

Protein attributes

Sequence length	590 AA.
Sequence status	Complete.
Protein existence	Evidence at protein 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. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro). Ref.3 Ref.4 Ref.6 Ref.7
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. Ref.6
Subcellular location	Cytoplasm By similarity. Nucleus. Cell membrane; Peripheral membrane protein. 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.6 Ref.7
Post-translational modification	Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity By similarity.
Disruption phenotype	No obvious phenotype due to the redundancy of GRK subtypes in the regulation of GPCR signaling. Deficient mice are viable and showed no anatomic or behavioral abnormalities, only a slight decrease in body temperature. However deficient mice shown altered central and lung M2 muscarinic receptor regulation, with normal heart M2 receptor regulation. GRK5 deficiency leads to a reduced hippocampal acetylcholine release and cholinergic hypofunction by selective impairment of desensitization of presynaptic M2/M4 autoreceptors and promotes beta-amyloid accumulation. Ref.3 Ref.4 Ref.7 Ref.8
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 negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB tachykinin receptor signaling pathway Inferred from electronic annotation. Source: Compara 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 from electronic annotation. Source: EC lipid binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
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_0000085972
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 Ref.5
	Modified residue	485	1	Phosphothreonine; by autocatalysis Ref.5
Experimental info
	Sequence conflict	154	1	K → T in AAH19379. Ref.2
	Sequence conflict	316	1	N → D in AAC09271. Ref.1
	Sequence conflict	353	1	A → D in AAC09271. Ref.1
	Sequence conflict	575	1	H → R in AAC09271. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q8VEB1 [UniParc]. Last modified May 24, 2004. Version 2. Checksum: F47D87397B1A2399	FASTA	590	67,732
	10 20 30 40 50 60 MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID RDYYSLCDKQ 70 80 90 100 110 120 PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA KGKEIMTKYL TPKSPVFIAQ 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 VLETEEVYSS 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 SNSKSSPTPK TSCNHRINSN HINSNSTGSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation." Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E., Lefkowitz R.J. J. Biol. Chem. 274:29381-29389(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. Strain: 129/SvJ.
[2]	"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].
[3]	"Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice." Gainetdinov R.R., Bohn L.M., Walker J.K., Laporte S.A., Macrae A.D., Caron M.G., Lefkowitz R.J., Premont R.T. Neuron 24:1029-1036(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[4]	"G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation." Walker J.K., Gainetdinov R.R., Feldman D.S., McFawn P.K., Caron M.G., Lefkowitz R.J., Premont R.T., Fisher J.T. Am. J. Physiol. 286:L312-L319(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[5]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, MASS SPECTROMETRY. Tissue: Liver.
[6]	"Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes." Martini J.S., Raake P., Vinge L.E., DeGeorge B.R. Jr., Chuprun J.K., Harris D.M., Gao E., Eckhart A.D., Pitcher J.A., Koch W.J. Proc. Natl. Acad. Sci. U.S.A. 105:12457-12462(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF HDAC5, INTERACTION WITH HDAC5.
[7]	"GRK5 deficiency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization." Liu J., Rasul I., Sun Y., Wu G., Li L., Premont R.T., Suo W.Z. J. Biol. Chem. 284:19564-19571(2009) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, FUNCTION.
[8]	"GRK5 deficiency accelerates beta-amyloid accumulation in Tg2576 mice via impaired cholinergic activity." Cheng S., Li L., He S., Liu J., Sun Y., He M., Grasing K., Premont R.T., Suo W.Z. J. Biol. Chem. 285:41541-41548(2010) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF040759 , AF040755, AF040756, AF040757, AF040758 Genomic DNA. Translation: AAC09271.1. AF040746 mRNA. Translation: AAC09267.1. BC019379 mRNA. Translation: AAH19379.1.
IPI	IPI00116589.
RefSeq	NP_061357.3. NM_018869.3.
UniGene	Mm.279400.
3D structure databases
ProteinModelPortal	Q8VEB1.
SMR	Q8VEB1. Positions 2-555.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-46262N.
PTM databases
PhosphoSite	Q8VEB1.
Proteomic databases
PaxDb	Q8VEB1.
PRIDE	Q8VEB1.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000003313; ENSMUSP00000003313; ENSMUSG00000003228.
GeneID	14773.
KEGG	mmu:14773.
Organism-specific databases
CTD	2869.
MGI	MGI:109161. Grk5.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00550000074318.
HOGENOM	HOG000006742.
HOVERGEN	HBG004532.
InParanoid	Q8VEB1.
KO	K08291.
OMA	EMMETEC.
OrthoDB	EOG4HHP24.
Gene expression databases
ArrayExpress	Q8VEB1.
Bgee	Q8VEB1.
CleanEx	MM_GRK5.
Genevestigator	Q8VEB1.
GermOnline	ENSMUSG00000003228. Mus musculus.
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	286873.
SOURCE	Search...

Entry information

Entry name

GRK5_MOUSE

Accession

Primary (citable) accession number: Q8VEB1
Secondary accession number(s): O70292, O70297

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 24, 2004
Last sequence update:	May 24, 2004
Last modified:	April 3, 2013
This is version 95 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program