KCC2D_RABIT
ID KCC2D_RABIT Reviewed; 533 AA.
AC O77708;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 2.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=Calcium/calmodulin-dependent protein kinase type II subunit delta;
DE Short=CaM kinase II subunit delta;
DE Short=CaMK-II subunit delta;
DE EC=2.7.11.17;
GN Name=CAMK2D;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=9852955; DOI=10.1016/s0378-1119(98)00422-3;
RA Takeuchi M., Fujisawa H.;
RT "New alternatively spliced variants of calmodulin-dependent protein kinase
RT II from rabbit liver.";
RL Gene 221:107-115(1998).
CC -!- FUNCTION: Calcium/calmodulin-dependent protein kinase involved in the
CC regulation of Ca(2+) homeostatis and excitation-contraction coupling
CC (ECC) in heart by targeting ion channels, transporters and accessory
CC proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release
CC from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and
CC K(+) channel transport. Targets also transcription factors and
CC signaling molecules to regulate heart function. In its activated form,
CC is involved in the pathogenesis of dilated cardiomyopathy and heart
CC failure. Contributes to cardiac decompensation and heart failure by
CC regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+)
CC channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2
CC repressor HDAC4, promoting its nuclear export and binding to 14-3-3
CC protein, and expression of MEF2 and genes involved in the hypertrophic
CC program. Is essential for left ventricular remodeling responses to
CC myocardial infarction. In pathological myocardial remodeling acts
CC downstream of the beta adrenergic receptor signaling cascade to
CC regulate key proteins involved in ECC. Regulates Ca(2+) influx to
CC myocytes by binding and phosphorylating the L-type Ca(2+) channel
CC subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and
CC regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+
CC channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart
CC failure. Phosphorylates phospholamban (PLN/PLB), an endogenous
CC inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR
CC Ca(2+) uptake that may be important in frequency-dependent acceleration
CC of relaxation (FDAR) and maintenance of contractile function during
CC acidosis. May participate in the modulation of skeletal muscle function
CC in response to exercise, by regulating SR Ca(2+) transport through
CC phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling
CC factor (By similarity). {ECO:0000250}.
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 autophosphorylation of Thr-287 which turns
CC the kinase in a constitutively active form and confers to the kinase a
CC Ca(2+)-independent activity.
CC -!- SUBUNIT: CAMK2 is composed of 4 different chains: alpha (CAMK2A), beta
CC (CAMK2B), gamma (CAMK2G), and delta (CAMK2D). The different isoforms
CC assemble into homo- or heteromultimeric holoenzymes composed of 12
CC subunits with two hexameric rings stacked one on top of the other.
CC Interacts with RRAD and CACNB2 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane, sarcolemma {ECO:0000305};
CC Peripheral membrane protein {ECO:0000305}; Cytoplasmic side
CC {ECO:0000305}. Sarcoplasmic reticulum membrane {ECO:0000305};
CC Peripheral membrane protein {ECO:0000305}; Cytoplasmic side
CC {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=Delta 1;
CC IsoId=O77708-1; Sequence=Displayed;
CC Name=2; Synonyms=Delta 2;
CC IsoId=O77708-2; Sequence=VSP_023106;
CC Name=3; Synonyms=Delta 3;
CC IsoId=O77708-3; Sequence=VSP_023105, VSP_023106;
CC Name=4; Synonyms=Delta 6;
CC IsoId=O77708-4; Sequence=VSP_023106, VSP_023107, VSP_023108;
CC Name=5; Synonyms=Delta 11;
CC IsoId=O77708-5; Sequence=VSP_023104;
CC Name=6; Synonyms=Delta 12;
CC IsoId=O77708-6; Sequence=VSP_023104, VSP_023107, VSP_023108;
CC -!- TISSUE SPECIFICITY: Expressed in liver. {ECO:0000269|PubMed:9852955}.
CC -!- DOMAIN: The CAMK2 protein kinases contain a unique C-terminal subunit
CC association domain responsible for oligomerization.
CC -!- PTM: Autophosphorylation of Thr-287 following activation by
CC Ca(2+)/calmodulin. Phosphorylation of Thr-287 locks the kinase into an
CC activated state (By similarity). {ECO:0000250}.
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; D14906; BAA28870.1; -; mRNA.
DR RefSeq; NP_001093424.1; NM_001099954.1. [O77708-2]
DR AlphaFoldDB; O77708; -.
DR SMR; O77708; -.
DR STRING; 9986.ENSOCUP00000021029; -.
DR GeneID; 100101557; -.
DR KEGG; ocu:100101557; -.
DR CTD; 817; -.
DR eggNOG; KOG0033; Eukaryota.
DR InParanoid; O77708; -.
DR OrthoDB; 330091at2759; -.
DR BRENDA; 2.7.11.17; 1749.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0042383; C:sarcolemma; IEA:UniProtKB-SubCell.
DR GO; GO:0033017; C:sarcoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0060341; P:regulation of cellular localization; ISS:UniProtKB.
DR InterPro; IPR013543; Ca/CaM-dep_prot_kinase-assoc.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR032710; NTF2-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; PF08332; CaMKII_AD; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF54427; SSF54427; 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 2: Evidence at transcript level;
KW Acetylation; Alternative splicing; ATP-binding; Calmodulin-binding;
KW Cell membrane; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Sarcoplasmic reticulum;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT CHAIN 2..533
FT /note="Calcium/calmodulin-dependent protein kinase type II
FT subunit delta"
FT /id="PRO_0000277819"
FT DOMAIN 14..272
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 283..292
FT /note="Autoinhibitory domain"
FT /evidence="ECO:0000250"
FT REGION 291..301
FT /note="Calmodulin-binding"
FT /evidence="ECO:0000250"
FT REGION 337..375
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 337..367
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 136
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 20..28
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 43
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 287
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 306
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 307
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 315
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 318
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q6PHZ2"
FT MOD_RES 319
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 364
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 365
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 367
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6PHZ2"
FT MOD_RES 370
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q6PHZ2"
FT MOD_RES 371
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 438
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 524
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13557"
FT MOD_RES 528
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6PHZ2"
FT VAR_SEQ 316
FT /note="Missing (in isoform 5 and isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_023104"
FT VAR_SEQ 328
FT /note="K -> KKRKSSSSVQMM (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_023105"
FT VAR_SEQ 329..362
FT /note="Missing (in isoform 2, isoform 3 and isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_023106"
FT VAR_SEQ 512
FT /note="K -> N (in isoform 4 and isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_023107"
FT VAR_SEQ 513..533
FT /note="Missing (in isoform 4 and isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_023108"
SQ SEQUENCE 533 AA; 60010 MW; 4CE3B54D96652B9E CRC64;
MASTTTCTRF TDEYQLFEEL GKGAFSVVRR CMKIPTGQEY AAKIINTKKL SARDHQKLER
EARICRLLKH PNIVRLHDSI SEEGFHYLVF DLVTGGELFE DIVAREYYSE ADASHCIQQI
LESVNHCHLN GIVHRDLKPE NLLLASKSKG AAVKLADFGL AIEVQGDQQA WFGFAGTPGY
LSPEVLRKDP YGKPVDMWAC GVILYILLVG YPPFWDEDQH RLYQQIKAGA YDFPSPEWDT
VTPEAKDLIN KMLTINPAKR ITASEALKHP WISHRATVAS MMHRQETVDC LKKFNARRKL
KGAILTTMLA TRNFSAAKSL LKKPDGVKIN NKANVVTSPK ENIPTPALEP QTTVIHNPDG
NKESTESSNT TIEDEDVKAR KQEIIKVTEQ LIEAINNGDF EAYTKICDPG LTAFEPEALG
NLVEGMDFHR FYFENALSKS NKPIHTIILN PHVHLVGEDA ACIAYIRLTQ YMDGSGMPKT
MQSEETRVWH RRDGKWQNVH FHRSGSPTVP IKPPCIPNGK ENYSGGTSLW QNI
