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Protein

Serine/threonine-protein kinase Chk1

Gene

Chek1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. This inhibits their activity through proteasomal degradation, nucleo-cytoplasmic shuttling and inhibition by proteins of the 13-3-3 family. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1, which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA (By similarity). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.By similarity4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei38ATPPROSITE-ProRule annotation1
Active sitei130Proton acceptorPROSITE-ProRule annotation1

Regions

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

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • histone kinase activity (H3-T11 specific) Source: UniProtKB
  • protein kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • apoptotic process involved in development Source: MGI
  • cellular response to DNA damage stimulus Source: MGI
  • cellular response to mechanical stimulus Source: Ensembl
  • chromatin-mediated maintenance of transcription Source: UniProtKB
  • DNA damage checkpoint Source: MGI
  • DNA damage induced protein phosphorylation Source: UniProtKB
  • DNA repair Source: MGI
  • G2/M transition of mitotic cell cycle Source: MGI
  • G2 DNA damage checkpoint Source: UniProtKB
  • inner cell mass cell proliferation Source: MGI
  • mitotic cell cycle checkpoint Source: MGI
  • negative regulation of mitotic nuclear division Source: UniProtKB
  • nucleus organization Source: MGI
  • peptidyl-threonine phosphorylation Source: UniProtKB
  • protein phosphorylation Source: MGI
  • regulation of cell proliferation Source: MGI
  • regulation of double-strand break repair via homologous recombination Source: UniProtKB
  • regulation of gene expression Source: MGI
  • regulation of histone H3-K9 acetylation Source: UniProtKB
  • regulation of mitotic centrosome separation Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, DNA damage, DNA repair

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1. 3474.
ReactomeiR-MMU-1433557. Signaling by SCF-KIT.
R-MMU-176187. Activation of ATR in response to replication stress.
R-MMU-5693607. Processing of DNA double-strand break ends.
R-MMU-5693616. Presynaptic phase of homologous DNA pairing and strand exchange.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.
R-MMU-69473. G2/M DNA damage checkpoint.
R-MMU-69601. Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase Chk1 (EC:2.7.11.1)
Alternative name(s):
CHK1 checkpoint homolog
Checkpoint kinase-1
Gene namesi
Name:Chek1
Synonyms:Chk1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:1202065. Chek1.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity
  • Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity

  • Note: Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B (By similarity).By similarity

GO - Cellular componenti

  • centrosome Source: UniProtKB
  • chromatin Source: UniProtKB
  • chromosome, telomeric region Source: Ensembl
  • condensed nuclear chromosome Source: UniProtKB
  • cytoplasm Source: UniProtKB-SubCell
  • extracellular space Source: MGI
  • intracellular membrane-bounded organelle Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • replication fork Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice die of apoptosis at the blastocyst stage.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi280S → A: Enhances cell cycle arrest. 1 Publication1
Mutagenesisi280S → E: Promotes mono and/or diubiquitination and nuclear exclusion. Reduces phosphorylation at S-345. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000858491 – 476Serine/threonine-protein kinase Chk1Add BLAST476

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei280Phosphoserine; by PKB/AKT11 Publication1
Modified residuei286PhosphoserineBy similarity1
Modified residuei296PhosphoserineBy similarity1
Modified residuei301PhosphoserineBy similarity1
Modified residuei317Phosphoserine; by ATM and ATR1 Publication1
Modified residuei345Phosphoserine; by ATR1 Publication1
Cross-linki436Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei463PhosphoserineCombined sources1
Modified residuei467PhosphoserineBy similarity1
Modified residuei468PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.2 Publications
Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion. The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation (By similarity). Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication (By similarity).By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO35280.
MaxQBiO35280.
PaxDbiO35280.
PeptideAtlasiO35280.
PRIDEiO35280.

PTM databases

iPTMnetiO35280.
PhosphoSitePlusiO35280.

Expressioni

Tissue specificityi

Found in all adult tissues tested. Elevated expression in testis, lung and spleen. 15.5 day old embryos show ubiquitous expression with strong expression in brain, liver, kidney, pancreas, intestine, thymus and lung.1 Publication

Developmental stagei

In the testis, present in cells undergoing meiosis I. Not detected in peripheral cells in seminiferous tubules that are undergoing pre-meiotic DNA synthesis or in late condensing or mature sperm.1 Publication

Gene expression databases

BgeeiENSMUSG00000032113.
CleanExiMM_CHEK1.
ExpressionAtlasiO35280. baseline and differential.
GenevisibleiO35280. MM.

Interactioni

Subunit structurei

Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (By similarity). Interacts with TIMELESS; DNA damage-dependent (PubMed:23418588). Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ. Interacts with CDK5RAP3; antagonizes CHEK1 (By similarity).By similarity1 Publication

Protein-protein interaction databases

BioGridi198694. 11 interactors.
IntActiO35280. 8 interactors.
MINTiMINT-1340615.
STRINGi10090.ENSMUSP00000034625.

Structurei

3D structure databases

ProteinModelPortaliO35280.
SMRiO35280.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini9 – 265Protein kinasePROSITE-ProRule annotationAdd BLAST257

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 265Interaction with CLSPNBy similarityAdd BLAST265
Regioni391 – 476Autoinhibitory regionBy similarityAdd BLAST86

Domaini

The autoinhibitory region (AIR) inhibits the activity of the kinase domain.By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0590. Eukaryota.
ENOG410XQ0D. LUCA.
GeneTreeiENSGT00680000099954.
HOGENOMiHOG000216658.
HOVERGENiHBG002590.
InParanoidiO35280.
KOiK02216.
OMAiGGFSKHI.
OrthoDBiEOG091G09E4.
PhylomeDBiO35280.
TreeFamiTF351441.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: O35280-1) [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
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRI TEEAVAVKIV DMKRAIDCPE
60 70 80 90 100
NIKKEICINK MLSHENVVKF YGHRREGHIQ YLFLEYCSGG ELFDRIEPDI
110 120 130 140 150
GMPEQDAQRF FHQLMAGVVY LHGIGITHRD IKPENLLLDE RDNLKISDFG
160 170 180 190 200
LATVFRHNNR ERLLNKMCGT LPYVAPELLK RKEFHAEPVD VWSCGIVLTA
210 220 230 240 250
MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA LLHKILVETP
260 270 280 290 300
SARITIPDIK KDRWYNKPLN RGAKRPRATS GGMSESSSGF SKHIHSNLDF
310 320 330 340 350
SPVNNGSSEE TVKFSSSQPE PRTGLSLWDT GPSNVDKLVQ GISFSQPTCP
360 370 380 390 400
EHMLVNSQLL GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETFEKL
410 420 430 440 450
GYQWKKSCMN QVTVSTTDRR NNKLIFKINL VEMDEKILVD FRLSKGDGLE
460 470
FKRHFLKIKG KLSDVVSSQK VWFPVT
Length:476
Mass (Da):54,381
Last modified:September 27, 2005 - v2
Checksum:i0642D238EB3C5BE3
GO
Isoform 2 (identifier: O35280-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-94: Missing.
     95-97: RIE → MEK

Note: No experimental confirmation available. 3 initiator methionines can be considered. If this isoform were to start at the first ATG, it would produce a 28 amino acid-long peptide, sharing the first 22 amino acids with the canonical sequence (isoform 1) and differing in the last 6 residues (VQLAVN -> ARHRDA). An initiation at this site could target the mRNA to nonsense-mediated mRNA decay and, in this case, the peptide would be produced at very low levels. The second possible translation initiation site would lead to the synthesis of the sequence shown in this entry as isoform 2. However, the Kozak sequence for this site is not optimal. Finally the third potential initiator methionine corresponds to position 167 in isoform 1 and would lead to the synthesis of a 310 amino acid-long protein identical to isoform 1 residues 167 through 476.
Show »
Length:382
Mass (Da):43,627
Checksum:i506D80B1AF404B7D
GO

Sequence cautioni

The sequence AAH37613 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti33E → Q in AAC53334 (PubMed:9278511).Curated1
Sequence conflicti50E → Q in AAC53334 (PubMed:9278511).Curated1
Sequence conflicti219 – 223SDWKE → LIVKK in AAB88853 (PubMed:9382850).Curated5
Sequence conflicti252A → S in AAB88853 (PubMed:9382850).Curated1
Sequence conflicti365S → F in AAC53334 (PubMed:9278511).Curated1
Sequence conflicti449 – 450LE → YN in AAB88853 (PubMed:9382850).Curated2

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0157911 – 94Missing in isoform 2. 1 PublicationAdd BLAST94
Alternative sequenceiVSP_01579295 – 97RIE → MEK in isoform 2. 1 Publication3

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF016583 mRNA. Translation: AAC53334.1.
AK011258 mRNA. Translation: BAB27500.1.
AK033179 mRNA. Translation: BAC28185.1.
AK045336 mRNA. Translation: BAC32315.1.
BC037613 mRNA. Translation: AAH37613.1. Different initiation.
AF032875 mRNA. Translation: AAB88853.1.
CCDSiCCDS22972.1. [O35280-1]
RefSeqiNP_031717.2. NM_007691.5. [O35280-1]
UniGeneiMm.16753.

Genome annotation databases

EnsembliENSMUST00000034625; ENSMUSP00000034625; ENSMUSG00000032113. [O35280-1]
ENSMUST00000172702; ENSMUSP00000134388; ENSMUSG00000032113. [O35280-1]
GeneIDi12649.
KEGGimmu:12649.
UCSCiuc009otv.1. mouse. [O35280-1]
uc009otx.2. mouse. [O35280-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF016583 mRNA. Translation: AAC53334.1.
AK011258 mRNA. Translation: BAB27500.1.
AK033179 mRNA. Translation: BAC28185.1.
AK045336 mRNA. Translation: BAC32315.1.
BC037613 mRNA. Translation: AAH37613.1. Different initiation.
AF032875 mRNA. Translation: AAB88853.1.
CCDSiCCDS22972.1. [O35280-1]
RefSeqiNP_031717.2. NM_007691.5. [O35280-1]
UniGeneiMm.16753.

3D structure databases

ProteinModelPortaliO35280.
SMRiO35280.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198694. 11 interactors.
IntActiO35280. 8 interactors.
MINTiMINT-1340615.
STRINGi10090.ENSMUSP00000034625.

PTM databases

iPTMnetiO35280.
PhosphoSitePlusiO35280.

Proteomic databases

EPDiO35280.
MaxQBiO35280.
PaxDbiO35280.
PeptideAtlasiO35280.
PRIDEiO35280.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000034625; ENSMUSP00000034625; ENSMUSG00000032113. [O35280-1]
ENSMUST00000172702; ENSMUSP00000134388; ENSMUSG00000032113. [O35280-1]
GeneIDi12649.
KEGGimmu:12649.
UCSCiuc009otv.1. mouse. [O35280-1]
uc009otx.2. mouse. [O35280-2]

Organism-specific databases

CTDi1111.
MGIiMGI:1202065. Chek1.

Phylogenomic databases

eggNOGiKOG0590. Eukaryota.
ENOG410XQ0D. LUCA.
GeneTreeiENSGT00680000099954.
HOGENOMiHOG000216658.
HOVERGENiHBG002590.
InParanoidiO35280.
KOiK02216.
OMAiGGFSKHI.
OrthoDBiEOG091G09E4.
PhylomeDBiO35280.
TreeFamiTF351441.

Enzyme and pathway databases

BRENDAi2.7.11.1. 3474.
ReactomeiR-MMU-1433557. Signaling by SCF-KIT.
R-MMU-176187. Activation of ATR in response to replication stress.
R-MMU-5693607. Processing of DNA double-strand break ends.
R-MMU-5693616. Presynaptic phase of homologous DNA pairing and strand exchange.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.
R-MMU-69473. G2/M DNA damage checkpoint.
R-MMU-69601. Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.

Miscellaneous databases

PROiO35280.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000032113.
CleanExiMM_CHEK1.
ExpressionAtlasiO35280. baseline and differential.
GenevisibleiO35280. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCHK1_MOUSE
AccessioniPrimary (citable) accession number: O35280
Secondary accession number(s): O54925, Q8CI40, Q9D0N2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: September 27, 2005
Last modified: November 30, 2016
This is version 163 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Haploinsufficient for the suppression of genomic instability and tumor progression.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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.