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P15791 (KCC2D_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 3, 2013. Version 122. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Calcium/calmodulin-dependent protein kinase type II subunit delta
Short name=CaM kinase II subunit delta
Short name=CaMK-II subunit delta
EC=2.7.11.17
Gene names
Name:Camk2d
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length533 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca2+ homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca2+ influx into the myocyte, Ca2+ release from the sarcoplasmic reticulum (SR), SR Ca2+ uptake and Na+ and K+ channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca2+ release via direct phosphorylation of RYR2 Ca2+ channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca2+ influx to myocytes by binding and phosphorylating the L-type Ca2+ channel subunit beta-2 CACNB2. In addition to Ca2+ channels, can target and regulate the cardiac sarcolemmal Na+ channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca2+ uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca2+ transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor By similarity. Ref.5 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

Activated by Ca2+/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows autophosphorylation of Thr-287 which turns the kinase in a constitutively active form and confers to the kinase a Ca2+-independent activity.

Subunit structure

CAMK2 is composed of 4 different chains: alpha (CAMK2A), beta (CAMK2B), gamma (CAMK2G), and delta (CAMK2D). The different isoforms assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other. Interacts with RRAD and CACNB2. Ref.7

Subcellular location

Cell membrane › sarcolemma; Peripheral membrane protein; Cytoplasmic side Probable. Sarcoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side Probable.

Isoform Delta 1: Nucleus.

Tissue specificity

Isoform Delta 1 is the predominant form in the brain, isoform Delta 2 and isoform Delta 3 predominate in the aorta and isoform Delta 4 in skeletal muscle.

Induction

By cocaine in cardiomyocytes. Ref.6

Domain

The CAMK2 protein kinases contain a unique C-terminal subunit association domain responsible for oligomerization.

Post-translational modification

Autophosphorylation of Thr-287 following activation by Ca2+/calmodulin. Phosphorylation of Thr-287 locks the kinase into an activated state By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Nucleus
Sarcoplasmic reticulum
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Calmodulin-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG1/S transition of mitotic cell cycle

Inferred from electronic annotation. Source: Compara

calcium ion transport

Inferred from electronic annotation. Source: Compara

cardiac muscle contraction

Inferred from electronic annotation. Source: Compara

peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Compara

positive regulation of cardiac muscle hypertrophy

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from electronic annotation. Source: Compara

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cellular localization

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of sodium ion transport

Inferred from electronic annotation. Source: Compara

   Cellular_componentT-tubule

Inferred from electronic annotation. Source: Compara

axon initial segment

Inferred from electronic annotation. Source: Compara

calcium- and calmodulin-dependent protein kinase complex

Traceable author statement PubMed 11264466. Source: UniProtKB

intercalated disc

Inferred from electronic annotation. Source: Compara

neuromuscular junction

Inferred from electronic annotation. Source: Compara

neuronal cell body

Inferred from electronic annotation. Source: Compara

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

sarcoplasmic reticulum membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

calmodulin-dependent protein kinase activity

Inferred from electronic annotation. Source: EC

Complete GO annotation...

Alternative products

This entry describes 7 isoforms produced by alternative splicing. [Align] [Select]
Isoform Delta 1 (identifier: P15791-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform Delta 2 (identifier: P15791-2)

The sequence of this isoform differs from the canonical sequence as follows:
     329-362: Missing.
Isoform Delta 3 (identifier: P15791-3)

The sequence of this isoform differs from the canonical sequence as follows:
     329-335: INNKANV → KRKSSSV
     337-359: Missing.
     360-362: GNK → QMM
Isoform Delta 4 (identifier: P15791-4)

The sequence of this isoform differs from the canonical sequence as follows:
     349-362: Missing.
Isoform Delta 5 (identifier: P15791-5)

The sequence of this isoform differs from the canonical sequence as follows:
     329-362: Missing.
     512-533: KPPCIPNGKENFSGGTSLWQNI → N
Isoform Delta 6 (identifier: P15791-6)

The sequence of this isoform differs from the canonical sequence as follows:
     512-533: KPPCIPNGKENFSGGTSLWQNI → N
Isoform Delta 7 (identifier: P15791-7)

The sequence of this isoform differs from the canonical sequence as follows:
     349-362: Missing.
     512-533: KPPCIPNGKENFSGGTSLWQNI → N

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 533532Calcium/calmodulin-dependent protein kinase type II subunit delta
PRO_0000086100

Regions

Domain14 – 272259Protein kinase
Nucleotide binding20 – 289ATP By similarity
Region283 – 29210Autoinhibitory domain By similarity
Region291 – 30111Calmodulin-binding By similarity

Sites

Active site1361Proton acceptor By similarity
Binding site431ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue2311Phosphotyrosine By similarity
Modified residue2871Phosphothreonine; by autocatalysis By similarity
Modified residue3061Phosphothreonine; by autocatalysis By similarity
Modified residue3071Phosphothreonine; by autocatalysis By similarity
Modified residue3191Phosphoserine By similarity
Modified residue3641Phosphoserine By similarity
Modified residue3711Phosphothreonine By similarity
Modified residue5241Phosphoserine By similarity

Natural variations

Alternative sequence329 – 36234Missing in isoform Delta 2 and isoform Delta 5.
VSP_004784
Alternative sequence329 – 3357INNKANV → KRKSSSV in isoform Delta 3.
VSP_004785
Alternative sequence337 – 35923Missing in isoform Delta 3.
VSP_004786
Alternative sequence349 – 36214Missing in isoform Delta 4 and isoform Delta 7.
VSP_004788
Alternative sequence360 – 3623GNK → QMM in isoform Delta 3.
VSP_004787
Alternative sequence512 – 53322KPPCI…LWQNI → N in isoform Delta 5, isoform Delta 6 and isoform Delta 7.
VSP_012043

Sequences

Sequence LengthMass (Da)Tools
Isoform Delta 1 [UniParc].

Last modified April 1, 1990. Version 1.
Checksum: E41BCB2B5A00E7CA

FASTA53360,081
        10         20         30         40         50         60 
MASTTTCTRF TDEYQLFEEL GKGAFSVVRR CMKIPTGQEY AAKIINTKKL SARDHQKLER 

        70         80         90        100        110        120 
EARICRLLKH PNIVRLHDSI SEEGFHYLVF DLVTGGELFE DIVAREYYSE ADASHCIQQI 

       130        140        150        160        170        180 
LESVNHCHLN GIVHRDLKPE NLLLASKSKG AAVKLADFGL AIEVQGDQQA WFGFAGTPGY 

       190        200        210        220        230        240 
LSPEVLRKDP YGKPVDMWAC GVILYILLVG YPPFWDEDQH RLYQQIKAGA YDFPSPEWDT 

       250        260        270        280        290        300 
VTPEAKDLIN KMLTINPAKR ITASEALKHP WICQRSTVAS MMHRQETVDC LKKFNARRKL 

       310        320        330        340        350        360 
KGAILTTMLA TRNFSAAKSL LKKPDGVKIN NKANVVTSPK ENIPTPALEP QTTVIHNPDG 

       370        380        390        400        410        420 
NKESTESSNT TIEDEDVKAR KQEIIKVTEQ LIEAINNGDF EAYTKICDPG LTAFEPEALG 

       430        440        450        460        470        480 
NLVEGMDFHR FYFENALPKI NKPIHTIILN PHVHLVGDDA ACIAYIRLTQ YMDGNGMPKT 

       490        500        510        520        530 
MQSEETRVWH RRDGKWQNIH FHRSGSPTVP IKPPCIPNGK ENFSGGTSLW QNI

« Hide

Isoform Delta 2 [UniParc].

Checksum: A200989BB0E857D6
Show »

FASTA49956,447
Isoform Delta 3 [UniParc].

Checksum: D21D28E2314C20AB
Show »

FASTA51057,709
Isoform Delta 4 [UniParc].

Checksum: D8D44571AB08AE3B
Show »

FASTA51958,549
Isoform Delta 5 [UniParc].

Checksum: D58353ACB0B7CEBF
Show »

FASTA47854,191
Isoform Delta 6 [UniParc].

Checksum: F84B958F92A2BF6C
Show »

FASTA51257,825
Isoform Delta 7 [UniParc].

Checksum: BC7AC4EE329AC27A
Show »

FASTA49856,293

References

« Hide 'large scale' references
[1]"Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs."
Tobimatsu T., Fujisawa H.
J. Biol. Chem. 264:17907-17912(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM DELTA 1).
[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] (ISOFORM DELTA 2).
Tissue: Prostate.
[3]"Identification of novel isoforms of the delta subunit of Ca2+/calmodulin-dependent protein kinase II. Differential expression in rat brain and aorta."
Schworer C.M., Rothblum L.I., Thekkumkara T.J., Singer H.A.
J. Biol. Chem. 268:14443-14449(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 314-533 (ISOFORMS DELTA 2; DELTA 3 AND DELTA 4).
Strain: Sprague-Dawley.
Tissue: Aorta and Skeletal muscle.
[4]"New isoforms of multifunctional calcium/calmodulin-dependent protein kinase II."
Mayer P., Moehlig M., Schatz H., Pfeiffer A.
FEBS Lett. 333:315-318(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 307-533 (ISOFORMS DELTA 1; DELTA 2; DELTA 4; DELTA 5; DELTA 6 AND DELTA 7).
[5]"Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes."
Hagemann D., Kuschel M., Kuramochi T., Zhu W., Cheng H., Xiao R.P.
J. Biol. Chem. 275:22532-22536(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF PLN/PLB.
[6]"Cocaine activates calcium/calmodulin kinase II and causes cardiomyocyte hypertrophy."
Henning R.J., Cuevas J.
J. Cardiovasc. Pharmacol. 48:802-813(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY COCAINE.
[7]"Rad GTPase deficiency leads to cardiac hypertrophy."
Chang L., Zhang J., Tseng Y.-H., Xie C.-Q., Ilany J., Bruning J.C., Sun Z., Zhu X., Cui T., Youker K.A., Yang Q., Day S.M., Kahn C.R., Chen Y.E.
Circulation 116:2976-2983(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RRAD.
[8]"CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses."
Zhang T., Kohlhaas M., Backs J., Mishra S., Phillips W., Dybkova N., Chang S., Ling H., Bers D.M., Maier L.S., Olson E.N., Brown J.H.
J. Biol. Chem. 282:35078-35087(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HDAC4 AND RYR2.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		J05072 mRNA. Translation: AAA40866.1.
BC107562 mRNA. Translation: AAI07563.1.
L13406 mRNA. Translation: AAA41479.1.
L13407 mRNA. Translation: AAA41480.1.
L13408 mRNA. Translation: AAA41481.1.
X77192 Genomic DNA. Translation: CAA54412.1.
X77193 Genomic DNA. Translation: CAA54413.1.
X77194 Genomic DNA. Translation: CAA54414.1.
X77195 Genomic DNA. Translation: CAA54415.1.
X75774 Genomic DNA. Translation: CAA53395.1.
IPIIPI00212226.
IPI00213583.
IPI00231612.
IPI00231613.
IPI00231614.
IPI00480684.
IPI00480796.
PIRA34366.
RefSeqNP_036651.1. NM_012519.2.
UniGeneRn.87208.

3D structure databases

ProteinModelPortalP15791.
SMRP15791. Positions 11-309, 370-508.
ModBaseSearch...

Protein-protein interaction databases

IntActP15791. 1 interaction.
MINTMINT-1892750.
STRING10116.ENSRNOP00000062118.

PTM databases

PhosphoSiteP15791.

Proteomic databases

PaxDbP15791.
PRIDEP15791.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000015564; ENSRNOP00000015559; ENSRNOG00000011589.
ENSRNOT00000016026; ENSRNOP00000016026; ENSRNOG00000011589.
ENSRNOT00000068198; ENSRNOP00000062625; ENSRNOG00000011589.
GeneID24246.
KEGGrno:24246.

Organism-specific databases

CTD817.
RGD2263. Camk2d.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00680000099653.
HOVERGENHBG108055.
KOK04515.

Enzyme and pathway databases

BRENDA2.7.11.17. 5301.

Gene expression databases

ArrayExpressP15791.
GenevestigatorP15791.

Family and domain databases

InterProIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR013543. Ca/CaM-dep_prot_kinase-assoc.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERPTHR24347. PTHR24347. 1 hit.
PfamPF08332. CaMKII_AD. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. Kinase_like. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

BindingDBP15791.
ChEMBLCHEMBL4987.
NextBio602745.

Entry information

Entry nameKCC2D_RAT
AccessionPrimary (citable) accession number: P15791
Secondary accession number(s): P97915 expand/collapse secondary AC list , P97916, Q3B7L0, Q63904, Q63905, Q63906, Q63907, Q63908
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: April 1, 1990
Last modified: April 3, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

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