Human Gene CAMK2D (uc003ibl.2) Description and Page Index
  Description: Homo sapiens calcium/calmodulin-dependent protein kinase II delta (CAMK2D), transcript variant 4, mRNA.
RefSeq Summary (NM_172115): The product of this gene belongs to the serine/threonine protein kinase family and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. In mammalian cells, the enzyme is composed of four different chains: alpha, beta, gamma, and delta. The product of this gene is a delta chain. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Distinct isoforms of this chain have different expression patterns.[provided by RefSeq, Nov 2008].
Transcript (Including UTRs)
   Position: hg19 chr4:114,378,344-114,683,083 Size: 304,740 Total Exon Count: 17 Strand: -
Coding Region
   Position: hg19 chr4:114,378,487-114,682,224 Size: 303,738 Coding Exon Count: 17 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-15

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr4:114,378,344-114,683,083)mRNA (may differ from genome)Protein (478 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
OMIMPubMedReactomeStanford SOURCETreefamUniProtKB

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Calcium/calmodulin-dependent protein kinase type II subunit delta; Short=CaM kinase II subunit delta; Short=CaMK-II subunit delta; EC=;
FUNCTION: Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) 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 Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) 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 Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) 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 Ca(2+) 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 Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor- coupling factor.
CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
ENZYME REGULATION: Activated by Ca(2+)/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 Ca(2+)-independent activity.
SUBUNIT: 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 (By similarity).
SUBCELLULAR LOCATION: Cell membrane, sarcolemma; Peripheral membrane protein; Cytoplasmic side (Probable). Sarcoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side (Probable).
TISSUE SPECIFICITY: Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle.
INDUCTION: Activity is induced in skeletal muscle during exercise.
DOMAIN: The CAMK2 protein kinases contain a unique C-terminal subunit association domain responsible for oligomerization.
PTM: Autophosphorylation of Thr-287 following activation by Ca(2+)/calmodulin. Phosphorylation of Thr-287 locks the kinase into an activated state.
MISCELLANEOUS: Expression of CAMK2D is significantly increased in patients suffering from dilated cardiomyopathy in PubMed:10189359.
SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.
SIMILARITY: Contains 1 protein kinase domain.
SEQUENCE CAUTION: Sequence=BAD92525.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): CAMK2D
CDC HuGE Published Literature: CAMK2D
Positive Disease Associations: Breath Tests , E-Selectin , Stroke
Related Studies:
  1. Breath Tests
    , , . [PubMed 0]
  2. Breath Tests
    , , . [PubMed 0]
  3. E-Selectin
    Andrew D Paterson et al. Arteriosclerosis, thrombosis, and vascular biology 2009, Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin., Arteriosclerosis, thrombosis, and vascular biology. [PubMed 19729612]
    ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.
           more ... click here to view the complete list

-  MalaCards Disease Associations
  MalaCards Gene Search: CAMK2D
Diseases sorted by gene-association score: dilated cardiomyopathy (8), cardiomyopathy (3)

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 36.45 RPKM in Brain - Cerebellar Hemisphere
Total median expression: 526.10 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -468.50859-0.545 Picture PostScript Text
3' UTR -25.80143-0.180 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR020636 - 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

Pfam Domains:
PF00069 - Protein kinase domain
PF07714 - Protein tyrosine kinase
PF08332 - Calcium/calmodulin dependent protein kinase II association domain
PF13474 - SnoaL-like domain
PF14534 - Domain of unknown function (DUF4440)

SCOP Domains:
47473 - EF-hand
56112 - Protein kinase-like (PK-like)
54427 - NTF2-like

Protein Data Bank (PDB) 3-D Structure
MuPIT help

- X-ray MuPIT

- X-ray MuPIT

- X-ray MuPIT
To conserve bandwidth, only the images from the first 3 structures are shown.
3GP2 - X-ray

ModBase Predicted Comparative 3D Structure on Q13557
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserNo orthologGenome BrowserGenome BrowserNo ortholog
Gene DetailsGene Details Gene DetailsGene Details 
Gene SorterGene Sorter Gene SorterGene Sorter 
 RGD FlyBaseWormBase 
 Protein Sequence Protein SequenceProtein Sequence 
 Alignment AlignmentAlignment 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0004672 protein kinase activity
GO:0004674 protein serine/threonine kinase activity
GO:0004683 calmodulin-dependent protein kinase activity
GO:0005088 Ras guanyl-nucleotide exchange factor activity
GO:0005515 protein binding
GO:0005516 calmodulin binding
GO:0005524 ATP binding
GO:0016301 kinase activity
GO:0016740 transferase activity
GO:0019871 sodium channel inhibitor activity
GO:0031432 titin binding
GO:0042802 identical protein binding
GO:0042803 protein homodimerization activity
GO:0044325 ion channel binding

Biological Process:
GO:0000165 MAPK cascade
GO:0001558 regulation of cell growth
GO:0002026 regulation of the force of heart contraction
GO:0003254 regulation of membrane depolarization
GO:0006357 regulation of transcription from RNA polymerase II promoter
GO:0006468 protein phosphorylation
GO:0007399 nervous system development
GO:0008016 regulation of heart contraction
GO:0010613 positive regulation of cardiac muscle hypertrophy
GO:0010649 regulation of cell communication by electrical coupling
GO:0010666 positive regulation of cardiac muscle cell apoptotic process
GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
GO:0016310 phosphorylation
GO:0018105 peptidyl-serine phosphorylation
GO:0018107 peptidyl-threonine phosphorylation
GO:0030154 cell differentiation
GO:0032469 endoplasmic reticulum calcium ion homeostasis
GO:0046777 protein autophosphorylation
GO:0051259 protein oligomerization
GO:0055119 relaxation of cardiac muscle
GO:0060314 regulation of ryanodine-sensitive calcium-release channel activity
GO:0060333 interferon-gamma-mediated signaling pathway
GO:0060341 regulation of cellular localization
GO:0071277 cellular response to calcium ion
GO:0086003 cardiac muscle cell contraction
GO:0086091 regulation of heart rate by cardiac conduction
GO:0098901 regulation of cardiac muscle cell action potential
GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction
GO:1901725 regulation of histone deacetylase activity
GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction
GO:1901897 regulation of relaxation of cardiac muscle
GO:1902306 negative regulation of sodium ion transmembrane transport
GO:1902514 regulation of calcium ion transmembrane transport via high voltage-gated calcium channel
GO:2000650 negative regulation of sodium ion transmembrane transporter activity

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0016020 membrane
GO:0016529 sarcoplasmic reticulum
GO:0030666 endocytic vesicle membrane
GO:0033017 sarcoplasmic reticulum membrane
GO:0042383 sarcolemma
GO:0043005 neuron projection
GO:0034704 calcium channel complex

-  Descriptions from all associated GenBank mRNAs
  AK025368 - Homo sapiens cDNA: FLJ21715 fis, clone COL10287, highly similar to AF071569 Homo sapiens multifunctional calcium/calmodulin-dependent protein kinase II delta2 isoform mRNA.
AK294517 - Homo sapiens cDNA FLJ53470 complete cds, highly similar to Calcium/calmodulin-dependent protein kinase type II delta chain (EC
AK055642 - Homo sapiens cDNA FLJ31080 fis, clone HSYRA2001615, highly similar to Calcium/calmodulin-dependent protein kinase type II delta chain (EC
AF071569 - Homo sapiens multifunctional calcium/calmodulin-dependent protein kinase II delta2 isoform mRNA, complete cds.
AB209288 - Homo sapiens mRNA for calcium/calmodulin-dependent protein kinase II delta isoform 1 variant protein.
BC032784 - Homo sapiens calcium/calmodulin-dependent protein kinase II delta, mRNA (cDNA clone MGC:44911 IMAGE:5178265), complete cds.
AY987011 - Homo sapiens calcium/calmodulin-dependent protein kinase II delta mRNA, complete cds, alternatively spliced.
EU176241 - Synthetic construct Homo sapiens clone IMAGE:100006427; FLH182803.01X; RZPDo839H07250D calcium/calmodulin-dependent protein kinase (CaM kinase) II delta (CAMK2D) gene, encodes complete protein.
KJ896536 - Synthetic construct Homo sapiens clone ccsbBroadEn_05930 CAMK2D gene, encodes complete protein.
KJ905159 - Synthetic construct Homo sapiens clone ccsbBroadEn_14565 CAMK2D gene, encodes complete protein.
DQ895255 - Synthetic construct Homo sapiens clone IMAGE:100009715; FLH182796.01L; RZPDo839C05139D calcium/calmodulin-dependent protein kinase (CaM kinase) II delta (CAMK2D) gene, encodes complete protein.
AB384909 - Synthetic construct DNA, clone: pF1KB4158, Homo sapiens CAMK2D gene for calcium/calmodulin-dependent protein kinase type II delta chain, complete cds, without stop codon, in Flexi system.
U50361 - Human calcium, calmodulin-dependent protein kinase II delta mRNA, partial cds.
U73738 - Human calcium/calmodulin-dependent protein kinase II delta E mRNA, partial cds.
EF139846 - Homo sapiens clone 1-4 calcium/calmodulin-dependent protein kinase II splice variant (CAMK2D) mRNA, partial sequence; alternatively spliced.
BC022558 - Homo sapiens calcium/calmodulin-dependent protein kinase II delta, mRNA (cDNA clone IMAGE:4794502), partial cds.
AJ252239 - Homo sapiens partial mRNA for calcium/calmodulin dependent protein kinase II delta (CaMK II delta gene).
JD065186 - Sequence 46210 from Patent EP1572962.
JD124637 - Sequence 105661 from Patent EP1572962.
JD075743 - Sequence 56767 from Patent EP1572962.
JD336951 - Sequence 317975 from Patent EP1572962.
JD222570 - Sequence 203594 from Patent EP1572962.
JD174177 - Sequence 155201 from Patent EP1572962.
JD203962 - Sequence 184986 from Patent EP1572962.
JD140763 - Sequence 121787 from Patent EP1572962.
JD142252 - Sequence 123276 from Patent EP1572962.
JD399317 - Sequence 380341 from Patent EP1572962.
JD193180 - Sequence 174204 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04012 - ErbB signaling pathway
hsa04020 - Calcium signaling pathway
hsa04114 - Oocyte meiosis
hsa04310 - Wnt signaling pathway
hsa04720 - Long-term potentiation
hsa04722 - Neurotrophin signaling pathway
hsa04740 - Olfactory transduction
hsa04912 - GnRH signaling pathway
hsa04916 - Melanogenesis
hsa05214 - Glioma

Reactome (by CSHL, EBI, and GO)

Protein Q13557 (Reactome details) participates in the following event(s):

R-HSA-442725 Activation of CaMKII
R-HSA-445367 CaMKII enters cytoplasm
R-HSA-444792 CaMKII enters nucleus
R-HSA-416320 Trafficking of GluR1-containing AMPA receptors
R-HSA-5082387 Phosphorylation of HSF1 at Ser230 induces transactivation
R-HSA-443475 Phosphorylation of CREB by CaMKII
R-HSA-442726 Raf activation
R-HSA-432172 Activation of NMDA receptor
R-HSA-432162 Unblocking of NMDA receptor
R-HSA-909552 Phosphorylation of STAT1 at Ser727
R-HSA-442760 Activation of RasGRF
R-HSA-432164 Ca2+ influx into the post-synaptic cell
R-HSA-442732 Ras activation
R-HSA-5672965 RAS GEFs promote RAS nucleotide exchange
R-HSA-442729 CREB phosphorylation through the activation of CaMKII
R-HSA-399719 Trafficking of AMPA receptors
R-HSA-438064 Post NMDA receptor activation events
R-HSA-3371571 HSF1-dependent transactivation
R-HSA-442742 CREB phosphorylation through the activation of Ras
R-HSA-399721 Glutamate binding, activation of AMPA receptors and synaptic plasticity
R-HSA-438066 Unblocking of NMDA receptor, glutamate binding and activation
R-HSA-442755 Activation of NMDA receptor and postsynaptic events
R-HSA-3371556 Cellular response to heat stress
R-HSA-877300 Interferon gamma signaling
R-HSA-112314 Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-442982 Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-2262752 Cellular responses to stress
R-HSA-913531 Interferon Signaling
R-HSA-112315 Transmission across Chemical Synapses
R-HSA-8953897 Cellular responses to external stimuli
R-HSA-1280215 Cytokine Signaling in Immune system
R-HSA-112316 Neuronal System
R-HSA-168256 Immune System
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-5684996 MAPK1/MAPK3 signaling
R-HSA-5683057 MAPK family signaling cascades
R-HSA-162582 Signal Transduction

-  Other Names for This Gene
  Alternate Gene Symbols: A8MVS8, CAMKD, KCC2D_HUMAN, NM_172115, NP_742125, Q13557, Q52PK4, Q59G21, Q8N553, Q9UGH6, Q9UQE9
UCSC ID: uc003ibl.2
RefSeq Accession: NM_172115
Protein: Q13557 (aka KCC2D_HUMAN)
CCDS: CCDS3704.1, CCDS47127.1, CCDS54797.1, CCDS3703.1, CCDS43263.1

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_172115.2
exon count: 17CDS single in 3' UTR: no RNA size: 2506
ORF size: 1437CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 3074.00frame shift in genome: no % Coverage: 97.33
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 103# strange splices: 0
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-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.