O14757 · CHK1_HUMAN
- ProteinSerine/threonine-protein kinase Chk1
- GeneCHEK1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids476 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856).
This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856).
Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856).
Binds to and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:12676583, PubMed:12676925, PubMed:12759351, PubMed:14559997, PubMed:14681206, PubMed:19734889, PubMed:9278511).
Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C (PubMed:9278511).
Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A (PubMed:12676583, PubMed:12676925, PubMed:12759351, PubMed:14681206, PubMed:19734889, PubMed:9278511).
Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A (PubMed:19734889, PubMed:20090422, PubMed:9278511).
Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression (PubMed:9278511).
Also phosphorylates NEK6 (PubMed:18728393).
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 (PubMed:15665856).
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 (PubMed:10673501, PubMed:15659650, PubMed:16511572).
Also promotes repair of DNA cross-links through phosphorylation of FANCE (PubMed:17296736).
Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A (PubMed:12660173, PubMed:12955071).
This may enhance chromatin assembly both in the presence or absence of DNA damage (PubMed:12660173, PubMed:12955071).
May also play a role in replication fork maintenance through regulation of PCNA (PubMed:18451105).
May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones (By similarity).
Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (By similarity).
May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest (PubMed:17380128).
Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (PubMed:31316063).
Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (PubMed:33108758).
Isoform 2
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Activity regulation
Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B (PubMed:11836499, PubMed:12766152, PubMed:16963448, PubMed:19330022).
Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity (PubMed:31316063).
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameSerine/threonine-protein kinase Chk1
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO14757
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B (PubMed:15311285).
Proteolytic cleavage at the C-terminus by SPRTN promotes removal from chromatin (PubMed:31316063).
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Oocyte/zygote/embryo maturation arrest 21 (OZEMA21)
- Note
- DescriptionAn autosomal dominant, female infertility disorder characterized by zygote development arrest due to failure of pronuclei fusion.
- See alsoMIM:620610
Natural variants in OZEMA21
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_089161 | 379 | R>Q | in OZEMA21; likely pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity | |
VAR_089162 | 420 | R>K | in OZEMA21; likely pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity | |
VAR_089163 | 442 | R>Q | in OZEMA21; pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 38 | Abolishes kinase activity. | ||||
Sequence: K → R | ||||||
Mutagenesis | 130 | Abolishes kinase activity. | ||||
Sequence: D → A | ||||||
Mutagenesis | 132 | Strong reduction of chromatin-associated CHK1 ubiquitination. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_021123 | 156 | in dbSNP:rs3731410 | |||
Sequence: R → Q | ||||||
Natural variant | VAR_040407 | 223 | in dbSNP:rs35817404 | |||
Sequence: E → V | ||||||
Natural variant | VAR_040408 | 312 | in dbSNP:rs34097480 | |||
Sequence: V → M | ||||||
Mutagenesis | 317 | Abrogates interaction with RAD51; when associated with A-345. Reduces phosphorylation and impairs activation by hydroxyurea and ionizing radiation. Abrogates nuclear retention upon checkpoint activation. Impairs interaction with FBXO6. | ||||
Sequence: S → A | ||||||
Mutagenesis | 317 | Enhances interaction with RAD51; when associated with E-345. | ||||
Sequence: S → E | ||||||
Mutagenesis | 344 | Impairs nuclear export. | ||||
Sequence: F → A | ||||||
Mutagenesis | 345 | Abrogates interaction with RAD51; when associated with A-317. Reduces phosphorylation and impairs activation by hydroxyurea and ionizing radiation. Impairs interaction with YWHAZ which is required for nuclear retention after checkpoint activation. | ||||
Sequence: S → A | ||||||
Mutagenesis | 345 | Enhances interaction with RAD51; when associated with E-317. | ||||
Sequence: S → E | ||||||
Mutagenesis | 353 | Impairs nuclear export. | ||||
Sequence: M → A | ||||||
Mutagenesis | 357 | No effect on phosphorylation induced by hydroxyurea. | ||||
Sequence: S → A | ||||||
Mutagenesis | 366 | No effect on phosphorylation induced by hydroxyurea. | ||||
Sequence: S → A | ||||||
Mutagenesis | 372 | In 3RE mutant. Disrupts the folding and/or conformation, allowing increased accessibility to FBXO6 component of SCF-type E3 ubiquitin ligase complex; when associated with E-376 and E-379. | ||||
Sequence: R → E | ||||||
Mutagenesis | 376 | In 3RE mutant. Disrupts the folding and/or conformation, allowing increased accessibility to FBXO6 component of SCF-type E3 ubiquitin ligase complex; when associated with E-372 and E-379. | ||||
Sequence: R → E | ||||||
Natural variant | VAR_089161 | 379 | in OZEMA21; likely pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity | |||
Sequence: R → Q | ||||||
Mutagenesis | 379 | In 3RE mutant. Disrupts the folding and/or conformation, allowing increased accessibility to FBXO6 component of SCF-type E3 ubiquitin ligase complex; when associated with E-372 and E-376. | ||||
Sequence: R → E | ||||||
Natural variant | VAR_089162 | 420 | in OZEMA21; likely pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity | |||
Sequence: R → K | ||||||
Mutagenesis | 436 | Enhances stability of the protein, probably by preventing ubiquitination at this site. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_089163 | 442 | in OZEMA21; pathogenic; results in failure of male and female pronuclei fusion when injected in mouse zygotes; increased kinase activity | |||
Sequence: R → Q | ||||||
Mutagenesis | 468 | No effect on phosphorylation induced by hydroxyurea. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_024571 | 471 | in dbSNP:rs506504 | |||
Sequence: I → V |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 615 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, cross-link, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000085848 | 1-476 | UniProt | Serine/threonine-protein kinase Chk1 | |||
Sequence: MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINKMLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVYLHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLKRREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLALLHKILVENPSARITIPDIKKDRWYNKPLKKGAKRPRVTSGGVSESPSGFSKHIQSNLDFSPVNSASSEENVKYSSSQPEPRTGLSLWDTSPSYIDKLVQGISFSQPTCPDHMLLNSQLLGTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETCEKLGYQWKKSCMNQVTISTTDRRNNKLIFKVNLLEMDDKILVDFRLSKGDGLEFKRHFLKIKGKLIDIVSSQKIWLPAT | |||||||
Cross-link | 132 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 279 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 280 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 280 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 286 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 286 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 288 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 296 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 296 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 301 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 301 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 305 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 307 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 308 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 316 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 317 | UniProt | Phosphoserine; by ATM and ATR | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 317 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 330 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 331 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 331 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 333 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 345 | UniProt | Phosphoserine; by ATM and ATR | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 390 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Cross-link | 436 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 467 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 468 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 468 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated by ATM in response to ionizing irradiation (PubMed:12588868, PubMed:12676583).
ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity (PubMed:11390642, PubMed:12446774, PubMed:12588868, PubMed:12660173, PubMed:12676583, PubMed:12676962, PubMed:14657349, PubMed:15665856, PubMed:15707391, PubMed:15870257, PubMed:25083873).
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 (PubMed:19716789).
Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention (PubMed:12676962).
Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest (PubMed:15870257).
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 (By similarity).
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. 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. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (PubMed:32357935).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1 (PubMed:16963448).
Interacts with BRCA1 (PubMed:11836499).
Interacts with and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511).
Interacts with FBXO6, which regulates CHEK1 (PubMed:19716789).
Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (PubMed:15870257).
Interacts with TIMELESS; DNA damage-dependent (PubMed:15798197).
Interacts with FEM1B; activates CHEK1 in response to stress (PubMed:19330022).
Interacts with TLK1 (PubMed:12660173).
Interacts with XPO1 and YWHAZ (PubMed:12676962).
Interacts with CDK5RAP3; antagonizes CHEK1 (PubMed:19223857).
Isoform 1
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | O14757 | BRCA1 P38398 | 3 | EBI-974488, EBI-349905 | |
BINARY | O14757 | CDC25C P30307 | 2 | EBI-974488, EBI-974439 | |
BINARY | O14757 | CLSPN Q9HAW4 | 5 | EBI-974488, EBI-1369377 | |
BINARY | O14757 | ERRFI1 Q9UJM3 | 2 | EBI-974488, EBI-2941912 | |
BINARY | O14757 | HLA-DRB5 Q30154 | 2 | EBI-974488, EBI-2798348 | |
BINARY | O14757 | HSP90AB1 P08238 | 3 | EBI-974488, EBI-352572 | |
BINARY | O14757 | RAD51 Q06609 | 3 | EBI-974488, EBI-297202 | |
BINARY | O14757 | RB1 P06400 | 3 | EBI-974488, EBI-491274 | |
BINARY | O14757 | SMURF1 Q9HCE7-2 | 4 | EBI-974488, EBI-9845742 | |
BINARY | O14757 | TIMELESS Q9UNS1 | 2 | EBI-974488, EBI-2212315 | |
BINARY | O14757 | YWHAB P31946 | 2 | EBI-974488, EBI-359815 | |
BINARY | O14757 | YWHAG P61981 | 8 | EBI-974488, EBI-359832 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-265 | Interaction with CLSPN | ||||
Sequence: MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINKMLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVYLHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLKRREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLALLHKILVENPSARITIPDIKKDRWY | ||||||
Domain | 9-265 | Protein kinase | ||||
Sequence: WDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINKMLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVYLHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLKRREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLALLHKILVENPSARITIPDIKKDRWY | ||||||
Region | 270-327 | Disordered | ||||
Sequence: KKGAKRPRVTSGGVSESPSGFSKHIQSNLDFSPVNSASSEENVKYSSSQPEPRTGLSL | ||||||
Compositional bias | 281-327 | Polar residues | ||||
Sequence: GGVSESPSGFSKHIQSNLDFSPVNSASSEENVKYSSSQPEPRTGLSL | ||||||
Region | 391-476 | Autoinhibitory region | ||||
Sequence: QCLKETCEKLGYQWKKSCMNQVTISTTDRRNNKLIFKVNLLEMDDKILVDFRLSKGDGLEFKRHFLKIKGKLIDIVSSQKIWLPAT |
Domain
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
O14757-1
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.
- Name1
- Length476
- Mass (Da)54,434
- Last updated2011-01-11 v2
- Checksum0ABD0FAB67E60F67
O14757-2
- Name2
- SynonymsChk1-short, Chk1-S
O14757-3
- Name3
- Differences from canonical
- 412-445: Missing
Computationally mapped potential isoform sequences
There are 7 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_044008 | 1-94 | in isoform 2 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_044009 | 95-97 | in isoform 2 | |||
Sequence: RIE → MEK | ||||||
Sequence conflict | 163 | in Ref. 5; BAG56691 | ||||
Sequence: L → S | ||||||
Sequence conflict | 220 | in Ref. 4; BAG61665 | ||||
Sequence: D → G | ||||||
Compositional bias | 281-327 | Polar residues | ||||
Sequence: GGVSESPSGFSKHIQSNLDFSPVNSASSEENVKYSSSQPEPRTGLSL | ||||||
Sequence conflict | 381 | in Ref. 4; BAG61665 | ||||
Sequence: F → L | ||||||
Alternative sequence | VSP_045075 | 412-445 | in isoform 3 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF016582 EMBL· GenBank· DDBJ | AAC51736.1 EMBL· GenBank· DDBJ | mRNA | ||
AF032874 EMBL· GenBank· DDBJ | AAB88852.1 EMBL· GenBank· DDBJ | mRNA | ||
AB032387 EMBL· GenBank· DDBJ | BAA84577.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
JF289264 EMBL· GenBank· DDBJ | AEB71796.1 EMBL· GenBank· DDBJ | mRNA | ||
AK292549 EMBL· GenBank· DDBJ | BAF85238.1 EMBL· GenBank· DDBJ | mRNA | ||
AK293143 EMBL· GenBank· DDBJ | BAG56691.1 EMBL· GenBank· DDBJ | mRNA | ||
AK299783 EMBL· GenBank· DDBJ | BAG61665.1 EMBL· GenBank· DDBJ | mRNA | ||
AF527555 EMBL· GenBank· DDBJ | AAM78553.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AB451222 EMBL· GenBank· DDBJ | BAG70036.1 EMBL· GenBank· DDBJ | mRNA | ||
AB451345 EMBL· GenBank· DDBJ | BAG70159.1 EMBL· GenBank· DDBJ | mRNA | ||
AP001132 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471065 EMBL· GenBank· DDBJ | EAW67644.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC004202 EMBL· GenBank· DDBJ | AAH04202.1 EMBL· GenBank· DDBJ | mRNA | ||
BC017575 EMBL· GenBank· DDBJ | AAH17575.1 EMBL· GenBank· DDBJ | mRNA |