KCC4_MOUSE
ID KCC4_MOUSE Reviewed; 469 AA.
AC P08414; Q61381;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1993, sequence version 2.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Calcium/calmodulin-dependent protein kinase type IV;
DE Short=CaMK IV;
DE EC=2.7.11.17;
DE AltName: Full=CaM kinase-GR;
GN Name=Camk4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=1893997; DOI=10.1016/0014-5793(91)80919-t;
RA Jones D.A., Glod J., Wilson-Shaw D., Hahn W.E., Sikela J.M.;
RT "cDNA sequence and differential expression of the mouse Ca2+/calmodulin-
RT dependent protein kinase IV gene.";
RL FEBS Lett. 289:105-109(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 240-469.
RX PubMed=2536634; DOI=10.1016/0888-7543(89)90309-1;
RA Sikela J.M., Law M.L., Kao F.-T., Hartz J.A., Wei Q., Hahn W.E.;
RT "Chromosomal localization of the human gene for brain Ca2+/calmodulin-
RT dependent protein kinase type IV.";
RL Genomics 4:21-27(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 315-469.
RC TISSUE=Brain;
RX PubMed=3033675; DOI=10.1073/pnas.84.9.3038;
RA Sikela J.M., Hahn W.E.;
RT "Screening an expression library with a ligand probe: isolation and
RT sequence of a cDNA corresponding to a brain calmodulin-binding protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:3038-3042(1987).
RN [4]
RP FUNCTION IN PHOSPHORYLATION OF CREB1.
RX PubMed=8195196; DOI=10.1016/s0021-9258(17)40710-1;
RA Enslen H., Sun P., Brickey D., Soderling S.H., Klamo E., Soderling T.R.;
RT "Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in
RT transcriptional regulation.";
RL J. Biol. Chem. 269:15520-15527(1994).
RN [5]
RP FUNCTION IN PHOSPHORYLATION OF CREBBP.
RX PubMed=9727976; DOI=10.1126/science.281.5382.1505;
RA Chawla S., Hardingham G.E., Quinn D.R., Bading H.;
RT "CBP: a signal-regulated transcriptional coactivator controlled by nuclear
RT calcium and CaM kinase IV.";
RL Science 281:1505-1509(1998).
RN [6]
RP FUNCTION IN PHOSPHORYLATION OF PRM2, TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=10932193; DOI=10.1038/78153;
RA Wu J.Y., Ribar T.J., Cummings D.E., Burton K.A., McKnight G.S., Means A.R.;
RT "Spermiogenesis and exchange of basic nuclear proteins are impaired in male
RT germ cells lacking Camk4.";
RL Nat. Genet. 25:448-452(2000).
RN [7]
RP FUNCTION.
RX PubMed=11572782; DOI=10.1016/s0092-8674(01)00497-4;
RA Kang H., Sun L.D., Atkins C.M., Soderling T.R., Wilson M.A., Tonegawa S.;
RT "An important role of neural activity-dependent CaMKIV signaling in the
RT consolidation of long-term memory.";
RL Cell 106:771-783(2001).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=11951046; DOI=10.1126/science.1071163;
RA Wu H., Kanatous S.B., Thurmond F.A., Gallardo T., Isotani E.,
RA Bassel-Duby R., Williams R.S.;
RT "Regulation of mitochondrial biogenesis in skeletal muscle by CaMK.";
RL Science 296:349-352(2002).
RN [9]
RP FUNCTION.
RX PubMed=18829949; DOI=10.1523/jneurosci.2625-08.2008;
RA Fukushima H., Maeda R., Suzuki R., Suzuki A., Nomoto M., Toyoda H.,
RA Wu L.J., Xu H., Zhao M.G., Ueda K., Kitamoto A., Mamiya N., Yoshida T.,
RA Homma S., Masushige S., Zhuo M., Kida S.;
RT "Upregulation of calcium/calmodulin-dependent protein kinase IV improves
RT memory formation and rescues memory loss with aging.";
RL J. Neurosci. 28:9910-9919(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-196 AND SER-439, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Calcium/calmodulin-dependent protein kinase that operates in
CC the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates,
CC mainly by phosphorylation, the activity of several transcription
CC activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal
CC roles in immune response, inflammation, and memory consolidation. In
CC the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes
CC selection threshold during T-cell ontogeny. In CD4 memory T-cells, is
CC required to link T-cell antigen receptor (TCR) signaling to the
CC production of IL2, IFNG and IL4 (through the regulation of CREB and
CC MEF2). Regulates the differentiation and survival phases of osteoclasts
CC and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and
CC the regulation of temporal expression of BCL2. Phosphorylates the
CC transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei
CC and contribute to memory consolidation and long term potentiation (LTP)
CC in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1
CC and MAPK14/p38 and stimulate transcription through the phosphorylation
CC of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A
CC and STMN1/OP18 (By similarity). May be involved in spermatogenesis.
CC {ECO:0000250, ECO:0000269|PubMed:10932193, ECO:0000269|PubMed:11572782,
CC ECO:0000269|PubMed:18829949, ECO:0000269|PubMed:8195196,
CC ECO:0000269|PubMed:9727976}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.17;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.17;
CC -!- ACTIVITY REGULATION: Activated by Ca(2+)/calmodulin. Binding of
CC calmodulin results in conformational change that relieves intrasteric
CC autoinhibition and allows phosphorylation of Thr-196 within the
CC activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-196 results
CC in a 10-20-fold increase in total activity to generate
CC Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-
CC terminus Ser-11 and Ser-12 is required for full activation. Inactivated
CC by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-
CC 196, thereby terminating autonomous activity and helping to maintain
CC the enzyme in its autoinhibited state.
CC -!- SUBUNIT: Monomer. Interacts with protein phosphatase 2A
CC (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to
CC Ca(2+)/calmodulin. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10932193}. Nucleus
CC {ECO:0000269|PubMed:10932193}. Note=Localized in hippocampal neuron
CC nuclei (By similarity). In spermatids, associated with chromatin and
CC nuclear matrix. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in brain and testis.
CC {ECO:0000269|PubMed:10932193, ECO:0000269|PubMed:11951046}.
CC -!- DOMAIN: The autoinhibitory domain overlaps with the calmodulin binding
CC region and interacts in the inactive folded state with the catalytic
CC domain as a pseudosubstrate. {ECO:0000250}.
CC -!- PTM: Phosphorylated by CaMKK1 and CaMKK2 on Thr-196. Dephosphorylated
CC by protein phosphatase 2A. Autophosphorylated on Ser-11 and Ser-12 (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Glycosylation at Ser-185 modulates the phosphorylation of CaMK4 at
CC Thr-196 and negatively regulates its activity toward CREB1 in basal
CC conditions and during early inomycin stimulation. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Male mice are infertile with impairment of
CC spermiogenesis in late elongating spermatids. The sequential deposition
CC of sperm basic nuclear proteins on chromatin is disrupted, with a
CC specific loss of protamine-2 and prolonged retention of Tnp2 in step-15
CC spermatids. {ECO:0000269|PubMed:10932193}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. CaMK subfamily. {ECO:0000305}.
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DR EMBL; M16206; AAA39933.1; -; mRNA.
DR EMBL; M64266; AAA37364.1; -; mRNA.
DR EMBL; J03057; AAA37366.1; -; mRNA.
DR EMBL; X58995; CAA41741.1; -; mRNA.
DR CCDS; CCDS29122.1; -.
DR PIR; S17656; S17656.
DR AlphaFoldDB; P08414; -.
DR SMR; P08414; -.
DR IntAct; P08414; 3.
DR MINT; P08414; -.
DR STRING; 10090.ENSMUSP00000046539; -.
DR GlyGen; P08414; 7 sites.
DR iPTMnet; P08414; -.
DR PhosphoSitePlus; P08414; -.
DR EPD; P08414; -.
DR MaxQB; P08414; -.
DR PaxDb; P08414; -.
DR PeptideAtlas; P08414; -.
DR PRIDE; P08414; -.
DR ProteomicsDB; 263584; -.
DR MGI; MGI:88258; Camk4.
DR eggNOG; KOG0032; Eukaryota.
DR InParanoid; P08414; -.
DR PhylomeDB; P08414; -.
DR BRENDA; 2.7.11.17; 3474.
DR Reactome; R-MMU-111932; CaMK IV-mediated phosphorylation of CREB.
DR Reactome; R-MMU-442729; CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde.
DR ChiTaRS; Camk4; mouse.
DR PRO; PR:P08414; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; P08414; protein.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0001650; C:fibrillar center; ISO:MGI.
DR GO; GO:0098982; C:GABA-ergic synapse; IDA:SynGO.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0098794; C:postsynapse; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0009931; F:calcium-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0005516; F:calmodulin binding; IBA:GO_Central.
DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0007616; P:long-term memory; ISS:UniProtKB.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; ISS:UniProtKB.
DR GO; GO:0007270; P:neuron-neuron synaptic transmission; IMP:MGI.
DR GO; GO:0006913; P:nucleocytoplasmic transport; IDA:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:MGI.
DR GO; GO:0099527; P:postsynapse to nucleus signaling pathway; IDA:SynGO.
DR GO; GO:0046777; P:protein autophosphorylation; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; IDA:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Adaptive immunity; ATP-binding; Calcium; Calmodulin-binding; Cytoplasm;
KW Glycoprotein; Immunity; Inflammatory response; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..469
FT /note="Calcium/calmodulin-dependent protein kinase type IV"
FT /id="PRO_0000086107"
FT DOMAIN 42..296
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 297..336
FT /note="Autoinhibitory domain"
FT /evidence="ECO:0000250"
FT REGION 302..319
FT /note="PP2A-binding"
FT /evidence="ECO:0000250"
FT REGION 318..337
FT /note="Calmodulin-binding"
FT /evidence="ECO:0000255"
FT REGION 336..469
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 336..363
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 386..408
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 414..428
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 429..443
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 160
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 48..56
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 71
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 11
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 12
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q16566"
FT MOD_RES 196
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 332
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P13234"
FT MOD_RES 337
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P13234"
FT MOD_RES 433
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P13234"
FT MOD_RES 439
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 53
FT /note="O-linked (GlcNAc) threonine"
FT /evidence="ECO:0000250"
FT CARBOHYD 54
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 133
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 185
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 340
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 341
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 352
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CONFLICT 278..280
FT /note="VLD -> CFGI (in Ref. 2; AAA37366)"
FT /evidence="ECO:0000305"
FT CONFLICT 302
FT /note="N -> T (in Ref. 2; AAA37366)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 469 AA; 52628 MW; CE1F98670822F975 CRC64;
MLKVTVPSCP SSPCSSVTAS TENLVPDYWI DGSNRDPLGD FFEVESELGR GATSIVYRCK
QKGTQKPYAL KVLKKTVDKK IVRTEIGVLL RLSHPNIIKL KEIFETPTEI SLVLELVTGG
ELFDRIVEKG YYSERDARDA VKQILEAVAY LHENGIVHRD LKPENLLYAT PAPDAPLKIA
DFGLSKIVEH QVLMKTVCGT PGYCAPEILR GCAYGPEVDM WSVGIITYIL LCGFEPFYDE
RGDQFMFRRI LNCEYYFISP WWDEVSLNAK DLVKKLIVLD PKKRLTTFQA LQHPWVTGKA
ANFVHMDTAQ KKLQEFNARR KLKAAVKAVV ASSRLGSASS SHTSIQENHK ASSDPPSTQD
AKDSTDLLGK KMQEEDQEED QVEAEASADE MRKLQSEEVE KDAGVKEEET SSMVPQDPED
ELETDDPEMK RDSEEKLKSV EEEMDPMTEE EAPDAGLGVP QQDAIQPEY
