Q91ZN7 (CHK1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase Chk1
EC=2.7.11.1

Alternative name(s):
CHK1 checkpoint homolog
Checkpoint kinase-1

Gene names

Name:	Chek1
Synonyms:	Chk1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	476 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	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. 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 similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	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.
Subunit structure	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. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ By similarity.
Subcellular location	Nucleus By similarity. Cytoplasm By similarity. Cytoplasm › cytoskeleton › centrosome 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.
Tissue specificity	Isoform 1 is expressed in brain, heart, liver, lung, skeletal muscle, spleen and testis. Isoform 2 is expressed only in liver. Ref.1
Domain	The autoinhibitory region (AIR) inhibits the activity of the kinase domain By similarity.
Post-translational modification	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 By similarity. 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. 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.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle DNA damage DNA repair
Cellular component	Cytoplasm Cytoskeleton Nucleus
Coding sequence diversity	Alternative promoter usage
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA damage induced protein phosphorylation Inferred from mutant phenotype PubMed 11278490. Source: RGD DNA repair Inferred from electronic annotation. Source: UniProtKB-KW G2 DNA damage checkpoint Inferred from mutant phenotype PubMed 11278490. Source: RGD G2/M transition of mitotic cell cycle Inferred from electronic annotation. Source: Compara cellular response to caffeine Inferred from expression pattern PubMed 11278490. Source: RGD cellular response to mechanical stimulus Inferred from electronic annotation. Source: Compara chromatin-mediated maintenance of transcription Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of mitosis Inferred from sequence or structural similarity. Source: UniProtKB regulation of S phase Inferred from mutant phenotype PubMed 12429946. Source: RGD regulation of cell proliferation Inferred from electronic annotation. Source: Compara regulation of double-strand break repair via homologous recombination Inferred from sequence or structural similarity. Source: UniProtKB regulation of histone H3-K9 acetylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of mitotic centrosome separation Inferred from sequence or structural similarity. Source: UniProtKB regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	centrosome Inferred from sequence or structural similarity. Source: UniProtKB chromatin Inferred from sequence or structural similarity. Source: UniProtKB chromosome, telomeric region Inferred from electronic annotation. Source: Compara condensed nuclear chromosome Inferred from sequence or structural similarity. Source: UniProtKB cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell replication fork Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW histone kinase activity (H3-T11 specific) Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative promoter usage. [Align] [Select]

Isoform 1 (identifier: Q91ZN7-1)

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 2 (identifier: Q91ZN7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-282: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 476	476	Serine/threonine-protein kinase Chk1		PRO_0000085850
Regions
	Domain	9 – 265	257	Protein kinase
	Nucleotide binding	15 – 23	9	ATP By similarity
	Region	1 – 265	265	Interaction with CLSPN By similarity
	Region	391 – 476	86	Autoinhibitory region By similarity
Sites
	Active site	130	1	Proton acceptor By similarity
	Binding site	38	1	ATP By similarity
Amino acid modifications
	Modified residue	280	1	Phosphoserine; by PKB/AKT1 By similarity
	Modified residue	286	1	Phosphoserine By similarity
	Modified residue	296	1	Phosphoserine By similarity
	Modified residue	301	1	Phosphoserine By similarity
	Modified residue	317	1	Phosphoserine; by ATM and ATR By similarity
	Modified residue	345	1	Phosphoserine; by ATM and ATR By similarity
	Cross-link	436		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Natural variations
	Alternative sequence	1 – 282	282	Missing in isoform 2.		VSP_015770

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: 5635614A3E5B4657	FASTA	476	54,428
	10 20 30 40 50 60 MAVPFVEDWD LVQTLGEGAY GEVQLAVNRI TEEAVAVKIV DMKRAIDCPE NIKKEICINK 70 80 90 100 110 120 MLNHENVVKF YGHRREGNIQ YLFLEYCSGG ELFDRIEPDI GMPEQDAQRF FHQLMAGVVY 130 140 150 160 170 180 LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRHNNR ERLLNKMCGT LPYVAPELLK 190 200 210 220 230 240 RKEFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA 250 260 270 280 290 300 LLHKILVENP SARITIPDIK KDRWYNKPLN RGAKRPRATS GGMSESSSGF SKHIHSNLDF 310 320 330 340 350 360 SPINSGSSEE NVKFSSSQPE PRTGLSLWDT GPSNVDKLVQ GISFSQPTCP DHMLVNSQLL 370 380 390 400 410 420 GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETFEKL GYQWKKSCMN QVTVSTMDRR 430 440 450 460 470 NNKLIFKINL VEMDEKILVD FRLSKGDGLE FKRHFLKIKG KLSDIVSSQK VWFPVT
	Isoform 2 [UniParc]. Checksum: 1E1B1CA8B0C4D7AC	FASTA	194	22,102
	10 20 30 40 50 60 MSESSSGFSK HIHSNLDFSP INSGSSEENV KFSSSQPEPR TGLSLWDTGP SNVDKLVQGI 70 80 90 100 110 120 SFSQPTCPDH MLVNSQLLGT PGSSQNPWQR LVKRMTRFFT KLDADKSYQC LKETFEKLGY 130 140 150 160 170 180 QWKKSCMNQV TVSTMDRRNN KLIFKINLVE MDEKILVDFR LSKGDGLEFK RHFLKIKGKL 190 SDIVSSQKVW FPVT

References

[1]	"Cloning and characterization of liver-specific isoform of Chk1 gene from rat." Shann Y.-J., Hsu M.-T. J. Biol. Chem. 276:48863-48870(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE PROMOTER USAGE, TISSUE SPECIFICITY. Tissue: Liver.
[2]	"The rat homolog of checkpoint kinase chk1." Wang X., Wang Y. Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Strain: Fischer 344.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF414135 mRNA. Translation: AAK98619.1. AF414136 mRNA. Translation: AAK98620.1. AF443592 mRNA. Translation: AAL37894.1.
IPI	IPI00210078. IPI00565261.
RefSeq	NP_536325.1. NM_080400.1.
UniGene	Rn.33267.
3D structure databases
ProteinModelPortal	Q91ZN7.
SMR	Q91ZN7. Positions 3-273.
ModBase	Search...
PTM databases
PhosphoSite	Q91ZN7.
Proteomic databases
PaxDb	Q91ZN7.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000011226; ENSRNOP00000011226; ENSRNOG00000008181.
GeneID	140583.
KEGG	rno:140583.
UCSC	RGD:620545. rat.
Organism-specific databases
CTD	1111.
RGD	620545. Chek1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00680000099954.
HOGENOM	HOG000216658.
HOVERGEN	HBG002590.
InParanoid	Q91ZN7.
KO	K02216.
OMA	GGFSKHI.
OrthoDB	EOG4001JD.
Enzyme and pathway databases
SABIO-RK	Q91ZN7.
Gene expression databases
Genevestigator	Q91ZN7.
GermOnline	ENSRNOG00000008181. Rattus norvegicus.
Family and domain databases
InterPro	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]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	620514.

Entry information

Entry name

CHK1_RAT

Accession

Primary (citable) accession number: Q91ZN7
Secondary accession number(s): Q91ZN6

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 27, 2005
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 97 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program