P05129 (KPCG_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein kinase C gamma type
Short name=PKC-gamma
EC=2.7.11.13

Gene names

Name:	PRKCG
Synonyms:	PKCG

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	697 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance of morphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation and degradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress By similarity. Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Ref.6
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Binds 3 calcium ions per subunit. The ions are bound to the C2 domain.
Enzyme regulation	Classical (or conventional) PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. Three specific sites; Thr-514 (activation loop of the kinase domain), Thr-655 (turn motif) and Thr-674 (hydrophobic region), need to be phosphorylated for its full activation.
Subunit structure	Interacts with GRIA4 By similarity. Interacts with CDCP1. Interacts with TP53INP1 and p53/TP53. Ref.5 Ref.6
Subcellular location	Cytoplasm By similarity. Cytoplasm › perinuclear region By similarity. Cell membrane; Peripheral membrane protein By similarity. Cell junction › synapse › synaptosome By similarity. Cell projection › dendrite By similarity. Note: Translocates to synaptic membranes on stimulation By similarity.
Tissue specificity	Expressed in Purkinje cells of the cerebellar cortex. Ref.14
Post-translational modification	Autophosphorylation on Thr-674 appears to regulate motor functions of junctophilins, JPH3 and JPH4 By similarity.
Involvement in disease	Spinocerebellar ataxia 14 (SCA14) [MIM:605361]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA14 is an autosomal dominant cerebellar ataxia (ADCA). Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 C2 domain. Contains 2 phorbol-ester/DAG-type zinc fingers. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Membrane Synapse Synaptosome
Coding sequence diversity	Polymorphism
Disease	Disease mutation Neurodegeneration Spinocerebellar ataxia
Domain	Repeat Zinc-finger
Ligand	ATP-binding Calcium Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of phospholipase C activity Traceable author statement. Source: Reactome cell death Inferred from electronic annotation. Source: UniProtKB-KW chemosensory behavior Inferred from electronic annotation. Source: Compara epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome innervation Inferred from electronic annotation. Source: Compara intracellular signal transduction Inferred from electronic annotation. Source: InterPro learning or memory Inferred from electronic annotation. Source: Compara negative regulation of neuron apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of protein catabolic process Inferred from direct assay PubMed 15808853. Source: HGNC negative regulation of protein ubiquitination Inferred from direct assay PubMed 15808853. Source: HGNC nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome platelet activation Traceable author statement. Source: Reactome positive regulation of mismatch repair Inferred from direct assay PubMed 15808853. Source: HGNC protein autophosphorylation Inferred from electronic annotation. Source: Compara response to morphine Inferred from sequence or structural similarity. Source: UniProtKB response to pain Inferred from sequence or structural similarity. Source: UniProtKB synaptic transmission Traceable author statement. Source: Reactome
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from sequence or structural similarity. Source: UniProtKB dendrite Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from electronic annotation. Source: Compara perinuclear region of cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB synaptic membrane Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW calcium-dependent protein kinase C activity Inferred from electronic annotation. Source: Compara protein kinase C activity Traceable author statement Ref.3. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 697

697

Protein kinase C gamma type

PRO_0000055689

Regions

Domain

170 – 260

91

C2

Domain

351 – 614

264

Protein kinase

Domain

615 – 685

71

AGC-kinase C-terminal

Zinc finger

35 – 85

51

Phorbol-ester/DAG-type 1

Zinc finger

100 – 150

51

Phorbol-ester/DAG-type 2

Nucleotide binding

357 – 365

9

ATP By similarity

Sites

Active site

480

1

Proton acceptor By similarity

Metal binding

186

1

Calcium 1; via carbonyl oxygen

Metal binding

187

1

Calcium 1

Metal binding

187

1

Calcium 2

Metal binding

193

1

Calcium 2

Metal binding

246

1

Calcium 1

Metal binding

246

1

Calcium 2

Metal binding

247

1

Calcium 2; via carbonyl oxygen

Metal binding

248

1

Calcium 1

Metal binding

248

1

Calcium 2

Metal binding

248

1

Calcium 3

Metal binding

251

1

Calcium 3

Metal binding

252

1

Calcium 3; via carbonyl oxygen

Metal binding

254

1

Calcium 1

Metal binding

254

1

Calcium 3

Binding site

380

1

ATP By similarity

Amino acid modifications

Modified residue

195

1

Phosphotyrosine By similarity

Modified residue

250

1

Phosphothreonine; by autocatalysis By similarity

Modified residue

312

1

Phosphotyrosine By similarity

Modified residue

322

1

Phosphoserine By similarity

Modified residue

330

1

Phosphoserine By similarity

Modified residue

514

1

Phosphothreonine; by PDPK1 Probable

Modified residue

518

1

Phosphothreonine By similarity

Modified residue

648

1

Phosphothreonine; by autocatalysis Potential

Modified residue

655

1

Phosphothreonine; by autocatalysis By similarity

Modified residue

674

1

Phosphothreonine; by autocatalysis By similarity

Modified residue

675

1

Phosphotyrosine; by SYK By similarity

Modified residue

687

1

Phosphoserine By similarity

Natural variations

Natural variant

101

1

H → Y in SCA14. Ref.14

VAR_017060

Natural variant

119

1

S → P in SCA14. Ref.14

VAR_017061

Natural variant

128

1

G → D in SCA14. Ref.14

VAR_017062

Natural variant

141

1

R → C. Ref.12

VAR_008755

Natural variant

415

1

H → Q. Ref.12

VAR_008756

Natural variant

523

1

A → D. Ref.12

VAR_008757

Natural variant

659

1

R → S. Ref.12

VAR_008758

Experimental info

Sequence conflict

314 – 317

4

RVRM → VSRT in AAA60102. Ref.3

Secondary structure

1

.

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.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

697

Helix Strand Turn

Details...

Turn

50 – 52

3

Beta strand

57 – 59

3

Turn

67 – 69

3

Helix

75 – 80

6

Turn

86 – 89

4

Beta strand

160 – 169

10

Beta strand

172 – 182

11

Beta strand

194 – 201

8

Beta strand

222 – 230

9

Helix

233 – 237

5

Beta strand

239 – 246

8

Beta strand

249 – 251

3

Beta strand

254 – 262

9

Helix

263 – 268

6

Beta strand

271 – 276

6

Helix

280 – 283

4

Sequences

	Sequence		Length	Mass (Da)
	P05129 [UniParc]. Last modified February 1, 1994. Version 3. Checksum: 3F911B5BEF713C41	FASTA	697	78,448
	10 20 30 40 50 60 MAGLGPGVGD SEGGPRPLFC RKGALRQKVV HEVKSHKFTA RFFKQPTFCS HCTDFIWGIG 70 80 90 100 110 120 KQGLQCQVCS FVVHRRCHEF VTFECPGAGK GPQTDDPRNK HKFRLHSYSS PTFCDHCGSL 130 140 150 160 170 180 LYGLVHQGMK CSCCEMNVHR RCVRSVPSLC GVDHTERRGR LQLEIRAPTA DEIHVTVGEA 190 200 210 220 230 240 RNLIPMDPNG LSDPYVKLKL IPDPRNLTKQ KTRTVKATLN PVWNETFVFN LKPGDVERRL 250 260 270 280 290 300 SVEVWDWDRT SRNDFMGAMS FGVSELLKAP VDGWYKLLNQ EEGEYYNVPV ADADNCSLLQ 310 320 330 340 350 360 KFEACNYPLE LYERVRMGPS SSPIPSPSPS PTDPKRCFFG ASPGRLHISD FSFLMVLGKG 370 380 390 400 410 420 SFGKVMLAER RGSDELYAIK ILKKDVIVQD DDVDCTLVEK RVLALGGRGP GGRPHFLTQL 430 440 450 460 470 480 HSTFQTPDRL YFVMEYVTGG DLMYHIQQLG KFKEPHAAFY AAEIAIGLFF LHNQGIIYRD 490 500 510 520 530 540 LKLDNVMLDA EGHIKITDFG MCKENVFPGT TTRTFCGTPD YIAPEIIAYQ PYGKSVDWWS 550 560 570 580 590 600 FGVLLYEMLA GQPPFDGEDE EELFQAIMEQ TVTYPKSLSR EAVAICKGFL TKHPGKRLGS 610 620 630 640 650 660 GPDGEPTIRA HGFFRWIDWE RLERLEIPPP FRPRPCGRSG ENFDKFFTRA APALTPPDRL 670 680 690 VLASIDQADF QGFTYVNPDF VHPDARSPTS PVPVPVM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Cui W.C., Yu L., Chu Y.Y., Wang J., Zheng L.H., Zhou G.J., Zhao S.Y. Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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]. Tissue: Brain.
[3]	"Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways." Coussens L., Parker P.J., Rhee L., Yang-Feng T.L., Chen E., Waterfield M.D., Francke U., Ullrich A. Science 233:859-866(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-317. Tissue: Brain.
[4]	"Activation and substrate specificity of the human protein kinase C alpha and zeta isoenzymes." Kochs G., Hummel R., Meyer D., Hug H., Marme D., Sarre T.F. Eur. J. Biochem. 216:597-606(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 162-697. Tissue: Hippocampus.
[5]	"The C2 domain of PKCdelta is a phosphotyrosine binding domain." Benes C.H., Wu N., Elia A.E.H., Dharia T., Cantley L.C., Soltoff S.P. Cell 121:271-280(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDCP1.
[6]	"Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage." Yoshida K., Liu H., Miki Y. J. Biol. Chem. 281:5734-5740(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TP53INP1 AND P53/TP53.
[7]	"Protein kinase C gamma (PKC gamma): function of neuron specific isotype." Saito N., Shirai Y. J. Biochem. 132:683-687(2002) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[8]	"Protein kinase C as a stress sensor." Barnett M.E., Madgwick D.K., Takemoto D.J. Cell. Signal. 19:1820-1829(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[10]	"Solution structure of the phorbol esters/diacylglycerol binding domain of protein kinase C gamma." RIKEN structural genomics initiative (RSGI) Submitted (DEC-2007) to the PDB data bank Cited for: STRUCTURE BY NMR OF 36-105.
[11]	"Crystal structure of C2 domain of protein kinase C gamma." Pike A.C.W., Amos A., Johansson C., Sobott F., Savitsky P., Berridge G., Fedorov O., Umeano C., Gorrec F., Bunkoczi G., Debreczeni J., Von Delft F., Arrowsmith C.H., Edwards A., Weigelt J., Sundstrom M., Knapp S. Submitted (APR-2007) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 154-295 IN COMPLEX WITH CALCIUM IONS.
[12]	"Segregation of a PRKCG mutation in two RP11 families." Al-Maghtheh M., Vithana E.N., Inglehearn C.F., Moore T., Bird A.C., Bhattacharya S.S. Am. J. Hum. Genet. 62:1248-1252(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CYS-141; GLN-415; ASP-523 AND SER-659.
[13]	"No mutations in the coding region of the PRKCG gene in three families with retinitis pigmentosa linked to the RP11 locus on chromosome 19q." Dryja T.P., McEvoy J., McGee T.L., Berson E.L. Am. J. Hum. Genet. 65:926-928(1999) [PubMed] [Europe PMC] [Abstract] Cited for: SHOWS THAT THE VARIANTS ARE NOT A CAUSE OF RP11.
[14]	"Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia." Chen D.-H., Brkanac Z., Verlinde C.L.M.J., Tan X.-J., Bylenok L., Nochlin D., Matsushita M., Lipe H., Wolff J., Fernandez M., Cimino P.J., Bird T.D., Raskind W.H. Am. J. Hum. Genet. 72:839-849(2003) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, VARIANTS SCA14 TYR-101; PRO-119 AND ASP-128.
+	Additional computationally mapped references.

Web resources

Mutations of the PRKCG gene

Retina International's Scientific Newsletter

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF345987 mRNA. Translation: AAK13533.1.
BC047876 mRNA. Translation: AAH47876.1.
M13977 mRNA. Translation: AAA60102.1.
Z15114 mRNA. Translation: CAA78820.1.

IPI

IPI01011898.

PIR

D24664.

RefSeq

NP_002730.1. NM_002739.3.

UniGene

Hs.631564.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2E73	NMR	-	A	36-105	[»]
2UZP	X-ray	2.00	A/B/C	154-295	[»]

ProteinModelPortal

P05129.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-39795N.

IntAct

P05129. 5 interactions.

MINT

MINT-222801.

STRING

9606.ENSP00000263431.

PTM databases

PhosphoSite

P05129.

Polymorphism databases

DMDM

462455.

Proteomic databases

PaxDb

P05129.

PeptideAtlas

P05129.

PRIDE

P05129.

Protocols and materials databases

DNASU

5582.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263431; ENSP00000263431; ENSG00000126583.

GeneID

5582.

KEGG

hsa:5582.

UCSC

uc002qcq.1. human.

Organism-specific databases

CTD

5582.

GeneCards

GC19P054382.

HGNC

HGNC:9402. PRKCG.

HPA

CAB013051.

MIM

176980. gene.
605361. phenotype.

neXtProt

NX_P05129.

Orphanet

98763. Spinocerebellar ataxia type 14.

PharmGKB

PA33766.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOVERGEN

HBG108317.

InParanoid

P05129.

KO

K02677.

OrthoDB

EOG40CHGD.

PhylomeDB

P05129.

Enzyme and pathway databases

BRENDA

2.7.11.13. 2681.

Pathway_Interaction_DB

endothelinpathway. Endothelins.
retinoic_acid_pathway. Retinoic acid receptors-mediated signaling.
nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
txa2pathway. Thromboxane A2 receptor signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_13685. Neuronal System.
REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P05129.

Bgee

P05129.

CleanEx

HS_PRKCG.

Genevestigator

P05129.

GermOnline

ENSG00000126583. Homo sapiens.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR000008. C2_Ca-dep.
IPR008973. C2_Ca/lipid-bd_dom_CaLB.
IPR020477. C2_dom.
IPR018029. C2_membr_targeting.
IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR017892. Pkinase_C.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR014375. Protein_kinase_C_a/b/g.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00130. C1_1. 2 hits.
PF00168. C2. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]

PIRSF

PIRSF000550. PKC_alpha. 1 hit.

PRINTS

PR00360. C2DOMAIN.
PR00008. DAGPEDOMAIN.

SMART

SM00109. C1. 2 hits.
SM00239. C2. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF49562. C2_CaLB. 1 hit.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS51285. AGC_KINASE_CTER. 1 hit.
PS50004. C2. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 2 hits.
PS50081. ZF_DAG_PE_2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P05129.

ChEMBL

CHEMBL2938.

EvolutionaryTrace

P05129.

GenomeRNAi

5582.

NextBio

21648.

PMAP-CutDB

P05129.

SOURCE

Search...

Entry information

Entry name

KPCG_HUMAN

Accession

Primary (citable) accession number: P05129

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	February 1, 1994
Last modified:	May 1, 2013
This is version 161 of the entry and version 3 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.