Q99986 (VRK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase VRK1
EC=2.7.11.1

Alternative name(s):
Vaccinia-related kinase 1

Gene names

Name:

VRK1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	396 AA.
Sequence status	Complete.
Protein existence	Evidence 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. Ref.3 Ref.5 Ref.7 Ref.8 Ref.10
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.14
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.8
Subcellular location	Cytoplasm. Nucleus. Cytoplasm › cytoskeleton › spindle By similarity. Note: Dispersed throughout the cell but not located on mitotic spindle or chromatids during mitosis. Ref.3 Ref.5 Ref.6 Ref.8
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.10 Ref.14
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.9
Sequence similarities	Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle Cell division Mitosis
Cellular component	Cytoplasm Cytoskeleton Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Golgi disassembly Inferred from direct assay Ref.10. Source: UniProtKB cell division Inferred from electronic annotation. Source: UniProtKB-KW mitosis Inferred from electronic annotation. Source: UniProtKB-KW protein autophosphorylation Inferred from direct assay Ref.14. Source: UniProtKB
Cellular_component	Golgi stack Inferred from direct assay Ref.10. Source: UniProtKB nucleolus Inferred from direct assay. Source: HPA spindle Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay Ref.14. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		4	EBI-1769146,EBI-1769146
ATF2	P15336	5	EBI-1769146,EBI-1170906
COIL	P38432	9	EBI-1769146,EBI-945751
JUN	P05412	4	EBI-1769146,EBI-852823
PLK3	Q9H4B4	12	EBI-1769146,EBI-751877
RAN	P62826	12	EBI-1769146,EBI-286642
TP53BP1	Q12888	8	EBI-1769146,EBI-396540

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 396

396

Serine/threonine-protein kinase VRK1

PRO_0000086803

Regions

Domain

37 – 317

281

Protein kinase

Nucleotide binding

43 – 51

9

ATP By similarity

Sites

Active site

177

1

Proton acceptor By similarity

Binding site

71

1

ATP By similarity

Amino acid modifications

Modified residue

342

1

Phosphoserine; by PLK3 Ref.10 Ref.11

Modified residue

355

1

Phosphothreonine; by autocatalysis

Experimental info

Mutagenesis

14

1

S → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

102

1

T → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

125

1

S → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

150

1

S → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

158

1

S → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

179

1

K → A: Does not affect phosphorylation at S-342. Ref.10

Mutagenesis

239

1

S → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

305

1

T → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

312

1

T → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

342

1

S → A: Abolishes phosphorylation by PLK3 and induction of Golgi fragmentation during mitosis. Strongly reduced autophosphorylation. Ref.10 Ref.14

Mutagenesis

353

1

T → A: Strongly reduced autophosphorylation. Ref.14

Mutagenesis

355

1

T → A: Does not abolish autophosphorylation. Ref.3

Mutagenesis

390

1

T → A: Does not abolish autophosphorylation. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

396

Helix Strand Turn

Details...

Turn

2 – 4

3

Beta strand

11 – 13

3

Beta strand

22 – 24

3

Beta strand

28 – 30

3

Beta strand

36 – 42

7

Beta strand

46 – 49

4

Beta strand

50 – 56

7

Beta strand

59 – 61

3

Beta strand

67 – 74

8

Helix

78 – 90

13

Helix

93 – 102

10

Beta strand

113 – 121

9

Beta strand

124 – 132

9

Beta strand

134 – 137

4

Helix

138 – 144

7

Turn

145 – 147

3

Helix

151 – 170

20

Helix

180 – 182

3

Beta strand

183 – 188

6

Beta strand

193 – 195

3

Helix

198 – 200

3

Beta strand

202 – 205

4

Helix

206 – 208

3

Turn

225 – 227

3

Helix

230 – 233

4

Helix

240 – 256

17

Helix

262 – 264

3

Helix

268 – 280

13

Helix

282 – 289

8

Beta strand

291 – 294

4

Helix

297 – 307

11

Beta strand

311 – 313

3

Helix

317 – 330

14

Beta strand

355 – 357

3

Sequences

	Sequence		Length	Mass (Da)
	Q99986 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 5640C624BF059949	FASTA	396	45,476
	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

References

	« Hide 'large scale' referencesShow '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: AUTOPHOSPHORYLATION, 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]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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.
[11]	"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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"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].
[13]	"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.
[14]	"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.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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.

IPI

IPI00019640.

RefSeq

NP_003375.1. NM_003384.2.

UniGene

Hs.422662.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KTY	NMR	-	A	1-360	[»]
2KUL	NMR	-	A	1-360	[»]
2LAV	NMR	-	A	1-361	[»]
3OP5	X-ray	2.40	A/B/C/D	3-364	[»]

ProteinModelPortal

Q99986.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99986. 11 interactions.

STRING

9606.ENSP00000216639.

PTM databases

PhosphoSite

Q99986.

Polymorphism databases

DMDM

45593726.

Proteomic databases

PaxDb

Q99986.

PeptideAtlas

Q99986.

PRIDE

Q99986.

Protocols and materials databases

DNASU

7443.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000216639; ENSP00000216639; ENSG00000100749.

GeneID

7443.

KEGG

hsa:7443.

UCSC

uc001yft.3. human.

Organism-specific databases

CTD

7443.

GeneCards

GC14P097263.

HGNC

HGNC:12718. VRK1.

HPA

HPA000660.
HPA017929.

MIM

602168. gene.
607596. phenotype.

neXtProt

NX_Q99986.

Orphanet

2254. Pontocerebellar hypoplasia type 1.

PharmGKB

PA37330.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG330134.

HOGENOM

HOG000069991.

HOVERGEN

HBG007532.

InParanoid

Q99986.

KO

K08816.

OMA

FMVMDRF.

OrthoDB

EOG4PG61C.

PhylomeDB

Q99986.

Gene expression databases

Bgee

Q99986.

CleanEx

HS_VRK1.

Genevestigator

Q99986.

GermOnline

ENSG00000100749. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 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

BindingDB

Q99986.

ChEMBL

CHEMBL1293199.

EvolutionaryTrace

Q99986.

GenomeRNAi

7443.

NextBio

29150.

SOURCE

Search...

Entry information

Entry name

VRK1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 124 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.