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UniProtKB - P48730 (KC1D_HUMAN)

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Protein

Casein kinase I isoform delta

Gene

CSNK1D

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.17 Publications

Miscellaneous

May be involved in Alzheimer disease by phosphorylating MAPT/TAU.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.
ATP + [tau protein] = ADP + [tau protein] phosphate.

Enzyme regulationi

Exhibits substrate-dependent heparin activation. Drug-mediated inhibition leads to a delay of the oscillations with the magnitude of this effect dependent upon the timing of drug administration. Inhibited by phosphorylation. Repressed by 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CKI-7), 4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide (D4476), 3,4-diaryl-isoxazoles and -imidazoles, and 4-(3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl) pyrimidin-2-ylamine (PF670462, PF670).10 Publications

Kineticsi

Maximal velocity nearly identical for the reactions with alpha-casein and PER2 peptide.
  1. KM=36.5 µM for alpha-casein1 Publication
  2. KM=635.8 µM for PER2 peptide1 Publication
  3. KM=180.6 µM for ATP1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei38ATPPROSITE-ProRule annotation1
    Active sitei128Proton acceptorPROSITE-ProRule annotation1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi15 – 23ATPPROSITE-ProRule annotation9

    GO - Molecular functioni

    • ATP binding Source: UniProtKB-KW
    • cadherin binding Source: BHF-UCL
    • glycoprotein binding Source: Ensembl
    • peptide binding Source: Ensembl
    • protein kinase activity Source: UniProtKB
    • protein serine/threonine kinase activity Source: ParkinsonsUK-UCL
    • tau-protein kinase activity Source: UniProtKB-EC
    Complete GO annotation...

    GO - Biological processi

    • cellular response to nerve growth factor stimulus Source: Ensembl
    • ciliary basal body docking Source: Reactome
    • circadian regulation of gene expression Source: UniProtKB
    • COPII vesicle coating Source: Reactome
    • endocytosis Source: GO_Central
    • G2/M transition of mitotic cell cycle Source: Reactome
    • Golgi organization Source: SYSCILIA_CCNET
    • microtubule nucleation Source: SYSCILIA_CCNET
    • non-motile cilium assembly Source: SYSCILIA_CCNET
    • peptidyl-serine phosphorylation Source: ParkinsonsUK-UCL
    • positive regulation of canonical Wnt signaling pathway Source: BHF-UCL
    • positive regulation of non-canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
    • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
    • positive regulation of protein phosphorylation Source: BHF-UCL
    • positive regulation of Wnt-mediated midbrain dopaminergic neuron differentiation Source: ParkinsonsUK-UCL
    • protein localization to centrosome Source: SYSCILIA_CCNET
    • protein localization to cilium Source: SYSCILIA_CCNET
    • protein localization to Golgi apparatus Source: SYSCILIA_CCNET
    • protein phosphorylation Source: UniProtKB
    • regulation of cell shape Source: GO_Central
    • regulation of circadian rhythm Source: UniProtKB
    • rRNA processing Source: Reactome
    • spindle assembly Source: UniProtKB
    • Wnt signaling pathway Source: UniProtKB-KW
    Complete GO annotation...

    Keywordsi

    Molecular functionKinase, Serine/threonine-protein kinase, Transferase
    Biological processBiological rhythms, Wnt signaling pathway
    LigandATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 2681.
    ReactomeiR-HSA-204005. COPII (Coat Protein 2) Mediated Vesicle Transport.
    R-HSA-2565942. Regulation of PLK1 Activity at G2/M Transition.
    R-HSA-380259. Loss of Nlp from mitotic centrosomes.
    R-HSA-380270. Recruitment of mitotic centrosome proteins and complexes.
    R-HSA-380284. Loss of proteins required for interphase microtubule organization from the centrosome.
    R-HSA-400253. Circadian Clock.
    R-HSA-5620912. Anchoring of the basal body to the plasma membrane.
    R-HSA-6791226. Major pathway of rRNA processing in the nucleolus and cytosol.
    R-HSA-8854518. AURKA Activation by TPX2.
    SABIO-RKiP48730.
    SignaLinkiP48730.
    SIGNORiP48730.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Casein kinase I isoform delta (EC:2.7.11.1)
    Short name:
    CKI-delta
    Short name:
    CKId
    Alternative name(s):
    Tau-protein kinase CSNK1D (EC:2.7.11.26)
    Gene namesi
    Name:CSNK1D
    Synonyms:HCKID
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
    Proteomesi
    • UP000005640 Componenti: Chromosome 17

    Organism-specific databases

    HGNCiHGNC:2452. CSNK1D.

    Subcellular locationi

    GO - Cellular componenti

    • centrosome Source: UniProtKB
    • cytosol Source: Reactome
    • endoplasmic reticulum-Golgi intermediate compartment membrane Source: Reactome
    • Golgi apparatus Source: UniProtKB
    • Golgi membrane Source: GOC
    • neuron projection Source: Ensembl
    • nucleoplasm Source: Reactome
    • nucleus Source: UniProtKB
    • perinuclear region of cytoplasm Source: UniProtKB
    • plasma membrane Source: UniProtKB
    • spindle Source: UniProtKB
    • spindle microtubule Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Cytoskeleton, Golgi apparatus, Membrane, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Advanced sleep phase syndrome, familial, 2 (FASPS2)2 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms.
    See also OMIM:615224
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_02907544T → A in FASPS2; strongly reduces kinase activity. 2 PublicationsCorresponds to variant dbSNP:rs104894561Ensembl.1
    Natural variantiVAR_06980146H → R in FASPS2; strongly reduces kinase activity. 1 PublicationCorresponds to variant dbSNP:rs397514693Ensembl.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi38K → M: Impaired kinase activity and abnormal subcellular localization with exclusive accumulation to the nucleus. 1 Publication1
    Mutagenesisi176T → I: Impaired kinase activity and abnormal subcellular localization with exclusive accumulation to the nucleus. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi1453.
    MalaCardsiCSNK1D.
    MIMi615224. phenotype.
    OpenTargetsiENSG00000141551.
    Orphaneti164736. Familial advanced sleep-phase syndrome.
    PharmGKBiPA26952.

    Chemistry databases

    ChEMBLiCHEMBL2828.
    GuidetoPHARMACOLOGYi1997.

    Polymorphism and mutation databases

    BioMutaiCSNK1D.
    DMDMi27923980.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001928331 – 415Casein kinase I isoform deltaAdd BLAST415

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei328PhosphoserineCombined sources1
    Modified residuei331PhosphoserineCombined sources1
    Modified residuei370PhosphoserineBy similarity1
    Modified residuei375Omega-N-methylarginineBy similarity1
    Modified residuei382PhosphoserineCombined sources1
    Modified residuei383PhosphoserineCombined sources1
    Modified residuei384PhosphoserineCombined sources1
    Modified residuei407PhosphoserineCombined sources1
    Modified residuei411PhosphoserineCombined sources1

    Post-translational modificationi

    Autophosphorylated on serine and threonine residues; this autophosphorylation represses activity. Reactivated by phosphatase-mediated dephosphorylation. May be dephosphorylated by PP1.

    Keywords - PTMi

    Methylation, Phosphoprotein

    Proteomic databases

    EPDiP48730.
    MaxQBiP48730.
    PaxDbiP48730.
    PeptideAtlasiP48730.
    PRIDEiP48730.
    TopDownProteomicsiP48730-1. [P48730-1]

    PTM databases

    iPTMnetiP48730.
    PhosphoSitePlusiP48730.

    Expressioni

    Tissue specificityi

    Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes.2 Publications

    Developmental stagei

    Highly present in extravillous trophoblast cells, which are present at the placenta implantation site and invade the decidua and decidual vessels.1 Publication

    Gene expression databases

    BgeeiENSG00000141551.
    CleanExiHS_CSNK1D.
    ExpressionAtlasiP48730. baseline and differential.
    GenevisibleiP48730. HS.

    Organism-specific databases

    HPAiCAB015410.

    Interactioni

    Subunit structurei

    Binds to DNMT1 and MAP1A (By similarity). Monomer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with PER1 and PER2 which may lead to their degradation. Interacts with MAPT/TAU, SNAPIN, DBNDD2, AIB1/NCOA3 and ESR1. AKAP9/AKAP450 binding promotes centrosomal subcellular location. Binds to tubulins in mitotic cells upon DNA damage.By similarity9 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • cadherin binding Source: BHF-UCL
    • glycoprotein binding Source: Ensembl
    Complete GO annotation...

    Protein-protein interaction databases

    BioGridi107837. 87 interactors.
    DIPiDIP-39735N.
    IntActiP48730. 43 interactors.
    MINTiMINT-1454355.
    STRINGi9606.ENSP00000324464.

    Chemistry databases

    BindingDBiP48730.

    Structurei

    Secondary structure

    1415
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi3 – 5Combined sources3
    Turni6 – 8Combined sources3
    Beta strandi9 – 16Combined sources8
    Beta strandi21 – 28Combined sources8
    Turni29 – 32Combined sources4
    Beta strandi33 – 41Combined sources9
    Beta strandi44 – 46Combined sources3
    Helixi49 – 59Combined sources11
    Beta strandi68 – 74Combined sources7
    Beta strandi77 – 83Combined sources7
    Helixi89 – 95Combined sources7
    Turni96 – 98Combined sources3
    Helixi102 – 121Combined sources20
    Helixi131 – 133Combined sources3
    Beta strandi134 – 136Combined sources3
    Helixi139 – 141Combined sources3
    Beta strandi145 – 147Combined sources3
    Beta strandi154 – 157Combined sources4
    Turni159 – 161Combined sources3
    Helixi177 – 179Combined sources3
    Helixi182 – 185Combined sources4
    Helixi192 – 208Combined sources17
    Turni212 – 215Combined sources4
    Helixi223 – 234Combined sources12
    Helixi237 – 240Combined sources4
    Turni241 – 243Combined sources3
    Helixi247 – 257Combined sources11
    Helixi266 – 279Combined sources14
    Turni289 – 292Combined sources4

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    		PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3UYSX-ray2.30A/B/C/D1-294[»]
    3UYTX-ray2.00A/B/C/D1-294[»]
    3UZPX-ray1.94A/B1-294[»]
    4HGTX-ray1.80A/B1-294[»]
    4HNFX-ray2.07A/B1-294[»]
    4KB8X-ray1.95A/B/C/D3-317[»]
    4KBAX-ray1.98A/B/C/D3-317[»]
    4KBCX-ray1.98A/B1-317[»]
    4KBKX-ray2.10A/B/C/D3-317[»]
    4TN6X-ray2.41A/B1-301[»]
    4TW9X-ray2.40A/B1-295[»]
    4TWCX-ray1.70A/B1-295[»]
    5IH4X-ray1.90A1-294[»]
    5IH5X-ray2.25A1-294[»]
    5IH6X-ray2.30A1-294[»]
    5MQVX-ray2.15A/B/C/D/E/F1-294[»]
    ProteinModelPortaliP48730.
    SMRiP48730.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini9 – 277Protein kinasePROSITE-ProRule annotationAdd BLAST269

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni278 – 364Centrosomal localization signal (CLS)Add BLAST87
    Regioni317 – 342AutoinhibitoryBy similarityAdd BLAST26

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.Curated

    Phylogenomic databases

    eggNOGiKOG1164. Eukaryota.
    ENOG410XPGP. LUCA.
    GeneTreeiENSGT00760000119040.
    HOGENOMiHOG000182055.
    HOVERGENiHBG000176.
    InParanoidiP48730.
    KOiK08959.
    PhylomeDBiP48730.
    TreeFamiTF300544.

    Family and domain databases

    InterProiView protein in InterPro
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR008271. Ser/Thr_kinase_AS.
    PfamiView protein in Pfam
    PF00069. Pkinase. 1 hit.
    SMARTiView protein in SMART
    SM00220. S_TKc. 1 hit.
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiView protein in PROSITE
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P48730-1) [UniParc]FASTAAdd to basket

    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.

    « Hide

            10         20         30         40         50
    MELRVGNRYR LGRKIGSGSF GDIYLGTDIA AGEEVAIKLE CVKTKHPQLH 
            60         70         80         90        100
    IESKIYKMMQ GGVGIPTIRW CGAEGDYNVM VMELLGPSLE DLFNFCSRKF 
           110        120        130        140        150
    SLKTVLLLAD QMISRIEYIH SKNFIHRDVK PDNFLMGLGK KGNLVYIIDF 
           160        170        180        190        200
    GLAKKYRDAR THQHIPYREN KNLTGTARYA SINTHLGIEQ SRRDDLESLG 
           210        220        230        240        250
    YVLMYFNLGS LPWQGLKAAT KRQKYERISE KKMSTPIEVL CKGYPSEFAT 
           260        270        280        290        300
    YLNFCRSLRF DDKPDYSYLR QLFRNLFHRQ GFSYDYVFDW NMLKFGASRA 
           310        320        330        340        350
    ADDAERERRD REERLRHSRN PATRGLPSTA SGRLRGTQEV APPTPLTPTS 
           360        370        380        390        400
    HTANTSPRPV SGMERERKVS MRLHRGAPVN ISSSDLTGRQ DTSRMSTSQI 
           410 
    PGRVASSGLQ SVVHR
    Length:415
    Mass (Da):47,330
    Last modified:January 27, 2003 - v2
    Checksum:iB97F1717A52466D2
    GO
    Isoform 2 (identifier: P48730-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         400-415: IPGRVASSGLQSVVHR → NSIPFEHHGK

    Show »
    Length:409
    Mass (Da):46,832
    Checksum:i970B55B1AF6B56DD
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti330A → D in AAC50807 (PubMed:8786104).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_02907544T → A in FASPS2; strongly reduces kinase activity. 2 PublicationsCorresponds to variant dbSNP:rs104894561Ensembl.1
    Natural variantiVAR_06980146H → R in FASPS2; strongly reduces kinase activity. 1 PublicationCorresponds to variant dbSNP:rs397514693Ensembl.1
    Natural variantiVAR_03645197S → C in breast cancer samples; infiltrating ductal carcinoma; somatic mutation. 2 Publications1
    Natural variantiVAR_042081401P → A1 PublicationCorresponds to variant dbSNP:rs56124628Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_010253400 – 415IPGRV…SVVHR → NSIPFEHHGK in isoform 2. 2 PublicationsAdd BLAST16

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    		U29171 mRNA. Translation: AAC50807.1.
    U31285 mRNA. Translation: AAC50808.1.
    AB091044 mRNA. Translation: BAC10903.1.
    AK291758 mRNA. Translation: BAF84447.1.
    EF015900 Genomic DNA. Translation: ABM64211.1.
    BC003558 mRNA. Translation: AAH03558.1.
    BC015775 mRNA. Translation: AAH15775.1.
    CCDSiCCDS11805.1. [P48730-1]
    CCDS11806.1. [P48730-2]
    PIRiG01876.
    RefSeqiNP_001884.2. NM_001893.4. [P48730-1]
    NP_620693.1. NM_139062.2. [P48730-2]
    UniGeneiHs.631725.

    Genome annotation databases

    EnsembliENST00000314028; ENSP00000324464; ENSG00000141551. [P48730-1]
    ENST00000392334; ENSP00000376146; ENSG00000141551. [P48730-2]
    GeneIDi1453.
    KEGGihsa:1453.
    UCSCiuc002kei.4. human. [P48730-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

    Entry informationi

    Entry nameiKC1D_HUMAN
    AccessioniPrimary (citable) accession number: P48730
    Secondary accession number(s): A2I2P2, Q96KZ6, Q9BTN5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: January 27, 2003
    Last modified: July 5, 2017
    This is version 181 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny 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.

    Miscellaneousi

    Caution

    Was shown to phosphorylate and activate DCK in vitro but probably not in vivo.1 Publication

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 17
      Human chromosome 17: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. SIMILARITY comments
      Index of protein domains and families