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Q99986 (VRK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Serine/threonine-protein kinase VRK1

EC=2.7.11.1
Alternative name(s):
Vaccinia-related kinase 1
Gene names
Name:VRK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length396 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosphorylates ATF2 which activates its transcriptional activity. Ref.3 Ref.5 Ref.6 Ref.8 Ref.9 Ref.11

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.15

Enzyme regulation

Active in presence of Mn2+, Mg2+ and Zn2+, but is not functional with Ca2+ or Cu2+. Has a higher affinity for Mn2+ than for Mg2+. RAN inhibits its autophosphorylation and its ability to phosphorylate histone H3. Ref.4 Ref.9

Subcellular location

Cytoplasm. Nucleus. Cytoplasmcytoskeletonspindle By similarity. Note: Dispersed throughout the cell but not located on mitotic spindle or chromatids during mitosis. Ref.3 Ref.5 Ref.6 Ref.7 Ref.9

Tissue specificity

Widely expressed. Highly expressed in fetal liver, testis and thymus. Ref.1

Post-translational modification

Autophosphorylated at various serine and threonine residues. Autophosphorylation does not impair its ability to phosphorylate p53/TP53. Phosphorylation by PLK3 leads to induction of Golgi fragmentation during mitosis. Ref.3 Ref.4 Ref.5 Ref.11 Ref.15

Involvement in disease

Pontocerebellar hypoplasia 1A (PCH1A) [MIM:607596]: A disorder characterized by an abnormally small cerebellum and brainstem, central and peripheral motor dysfunction from birth, gliosis and spinal cord anterior horn cells degeneration resembling infantile spinal muscular atrophy. Additional features include muscle hypotonia, congenital contractures and respiratory insufficiency that is evident at birth.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10

Sequence similarities

Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Cell division
Mitosis
   Cellular componentCytoplasm
Cytoskeleton
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processGolgi disassembly

Inferred from direct assay Ref.11. Source: UniProtKB

histone H3-S10 phosphorylation

Inferred from direct assay PubMed 22194607. Source: UniProt

histone H3-T3 phosphorylation

Inferred from direct assay PubMed 22194607. Source: UniProt

mitotic cell cycle

Traceable author statement. Source: Reactome

mitotic nuclear division

Inferred from electronic annotation. Source: UniProtKB-KW

mitotic nuclear envelope disassembly

Traceable author statement. Source: Reactome

mitotic nuclear envelope reassembly

Traceable author statement. Source: Reactome

protein autophosphorylation

Inferred from direct assay Ref.15. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 22194607. Source: UniProt

   Cellular_componentGolgi stack

Inferred from direct assay Ref.11. Source: UniProtKB

cytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement. Source: Reactome

nucleolus

Inferred from direct assay. Source: HPA

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 22194607. Source: UniProt

spindle

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

histone kinase activity (H3-S10 specific)

Inferred from direct assay PubMed 22194607. Source: UniProt

histone kinase activity (H3-T3 specific)

Inferred from direct assay PubMed 22194607. Source: UniProt

nucleosomal histone binding

Inferred from physical interaction PubMed 22194607. Source: UniProt

protein binding

Inferred from physical interaction Ref.6PubMed 15378002PubMed 15542844Ref.9Ref.11PubMed 21920476PubMed 22621922PubMed 24492002. Source: IntAct

protein kinase activity

Inferred from direct assay PubMed 22194607. Source: UniProt

protein serine/threonine kinase activity

Inferred from direct assay Ref.15. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 396396Serine/threonine-protein kinase VRK1
PRO_0000086803

Regions

Domain37 – 317281Protein kinase
Nucleotide binding43 – 519ATP By similarity

Sites

Active site1771Proton acceptor By similarity
Binding site711ATP By similarity

Amino acid modifications

Modified residue3421Phosphoserine; by PLK3 Ref.11 Ref.12
Modified residue3551Phosphothreonine; by autocatalysis Ref.4

Experimental info

Mutagenesis141S → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis1021T → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis1251S → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis1501S → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis1581S → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis1791K → A: Does not affect phosphorylation at S-342. Ref.11
Mutagenesis2391S → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis3051T → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis3121T → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis3421S → A: Abolishes phosphorylation by PLK3 and induction of Golgi fragmentation during mitosis. Strongly reduced autophosphorylation. Ref.11 Ref.15
Mutagenesis3531T → A: Strongly reduced autophosphorylation. Ref.15
Mutagenesis3551T → A: Does not abolish autophosphorylation. Ref.3
Mutagenesis3901T → A: Does not abolish autophosphorylation. Ref.3

Secondary structure

................................................................ 396
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99986 [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: 5640C624BF059949

FASTA39645,476
        10         20         30         40         50         60 
MPRVKAAQAG RQSSAKRHLA EQFAVGEIIT DMAKKEWKVG LPIGQGGFGC IYLADMNSSE 

        70         80         90        100        110        120 
SVGSDAPCVV KVEPSDNGPL FTELKFYQRA AKPEQIQKWI RTRKLKYLGV PKYWGSGLHD 

       130        140        150        160        170        180 
KNGKSYRFMI MDRFGSDLQK IYEANAKRFS RKTVLQLSLR ILDILEYIHE HEYVHGDIKA 

       190        200        210        220        230        240 
SNLLLNYKNP DQVYLVDYGL AYRYCPEGVH KEYKEDPKRC HDGTIEFTSI DAHNGVAPSR 

       250        260        270        280        290        300 
RGDLEILGYC MIQWLTGHLP WEDNLKDPKY VRDSKIRYRE NIASLMDKCF PEKNKPGEIA 

       310        320        330        340        350        360 
KYMETVKLLD YTEKPLYENL RDILLQGLKA IGSKDDGKLD LSVVENGGLK AKTITKKRKK 

       370        380        390 
EIEESKEPGV EDTEWSNTQT EEAIQTRSRT RKRVQK 

« Hide

References

« Hide 'large scale' references
[1]"Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to Vaccinia virus B1R kinase."
Nezu J., Oku A., Jones M.H., Shimane M.
Genomics 45:327-331(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
Tissue: Fetal liver.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain and Lung.
[3]"The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein."
Lopez-Borges S., Lazo P.A.
Oncogene 19:3656-3664(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, MUTAGENESIS OF SER-14; THR-102; SER-125; SER-150; SER-158; SER-239; THR-305; THR-312; THR-355 AND THR-390.
[4]"Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1."
Barcia R., Lopez-Borges S., Vega F.M., Lazo P.A.
Arch. Biochem. Biophys. 399:1-5(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-355, ENZYME REGULATION.
[5]"Characterization of three paralogous members of the Mammalian vaccinia related kinase family."
Nichols R.J., Traktman P.
J. Biol. Chem. 279:7934-7946(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION.
[6]"Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK."
Sevilla A., Santos C.R., Vega F.M., Lazo P.A.
J. Biol. Chem. 279:27458-27465(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[7]"The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines."
Blanco S., Klimcakova L., Vega F.M., Lazo P.A.
FEBS J. 273:2487-2504(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[8]"The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus."
Nichols R.J., Wiebe M.S., Traktman P.
Mol. Biol. Cell 17:2451-2464(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities."
Sanz-Garcia M., Lopez-Sanchez I., Lazo P.A.
Mol. Cell. Proteomics 7:2199-2214(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAN, ENZYME REGULATION.
[10]"Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene."
Renbaum P., Kellerman E., Jaron R., Geiger D., Segel R., Lee M., King M.C., Levy-Lahad E.
Am. J. Hum. Genet. 85:281-289(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN PCH1A.
[11]"Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces Golgi fragmentation."
Lopez-Sanchez I., Sanz-Garcia M., Lazo P.A.
Mol. Cell. Biol. 29:1189-1201(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT SER-342, MUTAGENESIS OF LYS-179 AND SER-342.
[12]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-342, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[13]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]"Human vaccinia-related kinase 1."
Structural genomics consortium (SGC)
Submitted (SEP-2010) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 3-364 IN COMPLEX WITH INHIBITOR.
[15]"NMR solution structure of human vaccinia-related kinase 1 (VRK1) reveals the C-terminal tail essential for its structural stability and autocatalytic activity."
Shin J., Chakraborty G., Bharatham N., Kang C., Tochio N., Koshiba S., Kigawa T., Kim W., Kim K.T., Yoon H.S.
J. Biol. Chem. 286:22131-22138(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR, CATALYTIC ACTIVITY, MUTAGENESIS OF SER-342 AND THR-353, AUTOPHOSPHORYLATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB000449 mRNA. Translation: BAA19108.1.
BC103761 mRNA. Translation: AAI03762.1.
BC112075 mRNA. Translation: AAI12076.1.
BC113510 mRNA. Translation: AAI13511.1.
CCDSCCDS9947.1.
RefSeqNP_003375.1. NM_003384.2.
UniGeneHs.422662.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2KTYNMR-A1-360[»]
2KULNMR-A1-360[»]
2LAVNMR-A1-361[»]
2RSVNMR-A1-396[»]
3OP5X-ray2.40A/B/C/D3-364[»]
ProteinModelPortalQ99986.
SMRQ99986. Positions 1-396.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid113282. 56 interactions.
IntActQ99986. 14 interactions.
MINTMINT-3060185.
STRING9606.ENSP00000216639.

Chemistry

BindingDBQ99986.
ChEMBLCHEMBL1293199.
GuidetoPHARMACOLOGY2275.

PTM databases

PhosphoSiteQ99986.

Polymorphism databases

DMDM45593726.

Proteomic databases

MaxQBQ99986.
PaxDbQ99986.
PeptideAtlasQ99986.
PRIDEQ99986.

Protocols and materials databases

DNASU7443.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000216639; ENSP00000216639; ENSG00000100749.
GeneID7443.
KEGGhsa:7443.
UCSCuc001yft.3. human.

Organism-specific databases

CTD7443.
GeneCardsGC14P097263.
HGNCHGNC:12718. VRK1.
HPAHPA000660.
HPA017929.
MIM602168. gene.
607596. phenotype.
neXtProtNX_Q99986.
Orphanet2254. Pontocerebellar hypoplasia type 1.
PharmGKBPA37330.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG330134.
HOGENOMHOG000069991.
HOVERGENHBG007532.
InParanoidQ99986.
KOK08816.
OMAYCMVQWL.
OrthoDBEOG7KSX83.
PhylomeDBQ99986.
TreeFamTF106473.

Enzyme and pathway databases

ReactomeREACT_115566. Cell Cycle.
REACT_21300. Mitotic M-M/G1 phases.
SignaLinkQ99986.

Gene expression databases

BgeeQ99986.
CleanExHS_VRK1.
GenevestigatorQ99986.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ99986.
GeneWikiVRK1.
GenomeRNAi7443.
NextBio29150.
PROQ99986.
SOURCESearch...

Entry information

Entry nameVRK1_HUMAN
AccessionPrimary (citable) accession number: Q99986
Secondary accession number(s): Q3SYL2
Entry history
Integrated into UniProtKB/Swiss-Prot: October 10, 2003
Last sequence update: May 1, 1997
Last modified: July 9, 2014
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM