Q13572 (ITPK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Inositol-tetrakisphosphate 1-kinase
EC=2.7.1.134

Alternative name(s):
Inositol 1,3,4-trisphosphate 5/6-kinase
Short name=Inositol-triphosphate 5/6-kinase
Short name=Ins(1,3,4)P(3) 5/6-kinase
EC=2.7.1.159

Gene names

Name:

ITPK1

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 › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	414 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Kinase that can phosphorylate various inositol polyphosphate such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3. Phosphorylates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca2+-activated Cl- channels, while Ins(1,3,4,5,6)P5 is not. Also phosphorylates Ins(1,3,4)P3 on O-5 and O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway. Also acts as an inositol polyphosphate phosphatase that dephosphorylate Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 to Ins(1,3,4)P3, and Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. May also act as an isomerase that interconverts the inositol tetrakisphosphate isomers Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 in the presence of ADP and magnesium. Probably acts as the rate-limiting enzyme of the InsP6 pathway. Modifies TNF-alpha-induced apoptosis by interfering with the activation of TNFRSF1A-associated death domain. Ref.4 Ref.5 Ref.7 Ref.13
Catalytic activity	ATP + 1D-myo-inositol 3,4,5,6-tetrakisphosphate = ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate. Ref.1 Ref.2 ATP + 1D-myo-inositol 1,3,4-trisphosphate = ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate. Ref.1 Ref.2 ATP + 1D-myo-inositol 1,3,4-trisphosphate = ADP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate.
Cofactor	Binds 2 magnesium ions per subunit. Ref.1
Subunit structure	Monomer. Interacts with GPS1/COPS1. Ref.6 Ref.13
Tissue specificity	Expressed in brain > heart > skeletal muscle = kidney = pancreas = liver = placenta > lung. In brain, it is expressed in cerebellum, cerebral cortex, medulla, spinal cord, occipital lobe, frontal lobe, temporal lobe and putamen. Ref.1
Post-translational modification	Acetylation by EP300 and CREBBP destabilizes ITPK1, and down-regulates enzymatic activity. Deacetylated by SIRT1. Ref.12
Sequence similarities	Belongs to the ITPK1 family. Contains 1 ATP-grasp domain.
Caution	Ref.4 detected some protein kinase activity and ability to phosphorylate transcription factors c-jun/JUN and ATF2. However, Ref.8 showed that it does not have protein kinase activity.
Biophysicochemical properties	Kinetic parameters: KM=0.3 µM for Ins(1,3,4)P3 Ref.2 KM=0.1 µM for Ins(3,4,5,6)P4 Vmax=320 pmol/min/µg enzyme with Ins(1,3,4)P3 as substrate Vmax=780 pmol/min/µg enzyme enzyme with Ins(3,4,5,6)P4 as substrate

Ontologies

Keywords
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Hydrolase Isomerase Kinase Transferase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Traceable author statement. Source: Reactome dephosphorylation Traceable author statement. Source: GOC inositol phosphate metabolic process Traceable author statement. Source: Reactome inositol trisphosphate metabolic process Inferred from electronic annotation. Source: InterPro signal transduction Traceable author statement Ref.1. Source: ProtInc small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW catalytic activity Traceable author statement Ref.1. Source: ProtInc inositol tetrakisphosphate 1-kinase activity Traceable author statement. Source: Reactome inositol-1,3,4,5,6-pentakisphosphate 1-phosphatase activity Traceable author statement. Source: Reactome inositol-1,3,4,6-tetrakisphosphate 1-phosphatase activity Traceable author statement. Source: Reactome inositol-1,3,4,6-tetrakisphosphate 6-phosphatase activity Traceable author statement. Source: Reactome inositol-1,3,4-trisphosphate 5-kinase activity Traceable author statement. Source: Reactome inositol-1,3,4-trisphosphate 6-kinase activity Traceable author statement. Source: Reactome inositol-3,4,6-trisphosphate 1-kinase activity Traceable author statement. Source: Reactome isomerase activity Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: Q13572-1)

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: Q13572-2)

The sequence of this isoform differs from the canonical sequence as follows:
     302-314: YEGVSEFFTDLLN → DCQVCFIEGWKTD
     315-414: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 414

414

Inositol-tetrakisphosphate 1-kinase

PRO_0000220833

Regions

Domain

117 – 325

209

ATP-grasp

Nucleotide binding

188 – 199

12

ATP

Sites

Metal binding

281

1

Magnesium 1

Metal binding

295

1

Magnesium 1

Metal binding

295

1

Magnesium 2

Metal binding

297

1

Magnesium 2

Binding site

18

1

1D-myo-inositol 1,3,4-trisphosphate By similarity

Binding site

106

1

ATP

Binding site

157

1

ATP

Binding site

167

1

1D-myo-inositol 1,3,4-trisphosphate By similarity

Binding site

199

1

1D-myo-inositol 1,3,4-trisphosphate By similarity

Binding site

214

1

ATP

Binding site

232

1

ATP

Binding site

236

1

ATP

Binding site

297

1

1D-myo-inositol 1,3,4-trisphosphate By similarity

Amino acid modifications

Modified residue

340

1

N6-acetyllysine; by EP300 and CREBBP Ref.12

Modified residue

383

1

N6-acetyllysine; by EP300 and CREBBP Ref.12

Modified residue

410

1

N6-acetyllysine; by EP300 and CREBBP Ref.12

Natural variations

Alternative sequence

302 – 314

13

YEGVS…TDLLN → DCQVCFIEGWKTD in isoform 2.

VSP_016478

Alternative sequence

315 – 414

100

Missing in isoform 2.

VSP_016479

Experimental info

Mutagenesis

18

1

K → A: Loss of kinase activity. Ref.9

Mutagenesis

58

1

H → A: No effect. Ref.9

Mutagenesis

59

1

K → A: Loss of kinase activity. Ref.9

Mutagenesis

106

1

R → A: Loss of kinase activity. Ref.8 Ref.9

Mutagenesis

157

1

K → A: Loss of kinase activity. Ref.8

Mutagenesis

162

1

H → Q: Loss of kinase activity. Ref.9

Mutagenesis

163

1

G → A or P: Loss of kinase activity. Ref.8 Ref.9

Mutagenesis

163

1

G → A: No effect. Ref.8 Ref.9

Mutagenesis

167

1

H → A or Q: Loss of kinase activity. Ref.9

Mutagenesis

188

1

Q → A: No effect. Ref.9

Mutagenesis

193

1

H → A: Loss of kinase activity. Ref.9

Mutagenesis

199

1

K → A: Loss of kinase activity. Ref.9

Mutagenesis

212

1

R → A: Loss of kinase activity. Ref.9

Mutagenesis

214

1

S → A: Loss of kinase activity. Ref.9

Mutagenesis

215

1

L → A: No effect. Ref.9

Mutagenesis

281

1

D → A: Loss of kinase activity. Ref.8

Mutagenesis

295

1

D → A: Loss of kinase activity. Ref.8

Mutagenesis

297

1

N → A or L: Loss of kinase activity. Ref.8 Ref.9

Mutagenesis

297

1

N → D: Induces a strong reduction in kinase activity. Ref.8 Ref.9

Mutagenesis

301

1

G → A: Loss of kinase activity. Ref.9

Sequence conflict

356

1

S → N in AAC50483. Ref.1

Secondary structure

1

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414

Helix Strand Turn

Details...

Helix

1 – 5

5

Beta strand

9 – 13

5

Helix

16 – 22

7

Helix

24 – 32

9

Turn

33 – 35

3

Beta strand

37 – 40

4

Helix

48 – 50

3

Beta strand

54 – 58

5

Helix

61 – 68

8

Helix

72 – 87

16

Beta strand

91 – 95

5

Helix

97 – 102

6

Helix

106 – 120

15

Beta strand

130 – 133

4

Helix

138 – 140

3

Helix

141 – 147

7

Beta strand

152 – 157

6

Turn

164 – 167

4

Beta strand

168 – 172

5

Helix

175 – 177

3

Beta strand

185 – 189

5

Beta strand

196 – 203

8

Beta strand

206 – 213

8

Beta strand

228 – 231

4

Helix

232 – 234

3

Helix

243 – 245

3

Helix

259 – 273

15

Beta strand

277 – 284

8

Turn

286 – 288

3

Beta strand

291 – 299

9

Helix

308 – 324

17

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 6, 2005. Version 2. Checksum: E89E2EE11971278E	FASTA	414	45,621
	10 20 30 40 50 60 MQTFLKGKRV GYWLSEKKIK KLNFQAFAEL CRKRGMEVVQ LNLSRPIEEQ GPLDVIIHKL 70 80 90 100 110 120 TDVILEADQN DSQSLELVHR FQEYIDAHPE TIVLDPLPAI RTLLDRSKSY ELIRKIEAYM 130 140 150 160 170 180 EDDRICSPPF MELTSLCGDD TMRLLEKNGL TFPFICKTRV AHGTNSHEMA IVFNQEGLNA 190 200 210 220 230 240 IQPPCVVQNF INHNAVLYKV FVVGESYTVV QRPSLKNFSA GTSDRESIFF NSHNVSKPES 250 260 270 280 290 300 SSVLTELDKI EGVFERPSDE VIRELSRALR QALGVSLFGI DIIINNQTGQ HAVIDINAFP 310 320 330 340 350 360 GYEGVSEFFT DLLNHIATVL QGQSTAMAAT GDVALLRHSK LLAEPAGGLV GERTCSASPG 370 380 390 400 410 CCGSMMGQDA PWKAEADAGG TAKLPHQRLG CNAGVSPSFQ QHCVASLATK ASSQ
	Isoform 2 [UniParc]. Checksum: DD10427FADBBB3E0	FASTA	314	35,632
	10 20 30 40 50 60 MQTFLKGKRV GYWLSEKKIK KLNFQAFAEL CRKRGMEVVQ LNLSRPIEEQ GPLDVIIHKL 70 80 90 100 110 120 TDVILEADQN DSQSLELVHR FQEYIDAHPE TIVLDPLPAI RTLLDRSKSY ELIRKIEAYM 130 140 150 160 170 180 EDDRICSPPF MELTSLCGDD TMRLLEKNGL TFPFICKTRV AHGTNSHEMA IVFNQEGLNA 190 200 210 220 230 240 IQPPCVVQNF INHNAVLYKV FVVGESYTVV QRPSLKNFSA GTSDRESIFF NSHNVSKPES 250 260 270 280 290 300 SSVLTELDKI EGVFERPSDE VIRELSRALR QALGVSLFGI DIIINNQTGQ HAVIDINAFP 310 GDCQVCFIEG WKTD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression of the recombinant enzyme." Wilson M.P., Majerus P.W. J. Biol. Chem. 271:11904-11910(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ENZYME ACTIVITY, COFACTOR, TISSUE SPECIFICITY. Tissue: Brain.
[2]	"Multitasking in signal transduction by a promiscuous human Ins(3,4,5,6)P(4) 1-kinase/Ins(1,3,4)P(3) 5/6-kinase." Yang X., Shears S.B. Biochem. J. 351:551-555(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
[3]	"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] (ISOFORMS 1 AND 2). Tissue: Eye and Muscle.
[4]	"Inositol 1,3,4-trisphosphate 5/6-kinase is a protein kinase that phosphorylates the transcription factors c-Jun and ATF-2." Wilson M.P., Sun Y., Cao L., Majerus P.W. J. Biol. Chem. 276:40998-41004(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PUTATIVE FUNCTION AS PROTEIN KINASE.
[5]	"Regulation of Ins(3,4,5,6)P(4) signaling by a reversible kinase/phosphatase." Ho M.W.Y., Yang X., Carew M.A., Zhang T., Hua L., Kwon Y.-U., Chung S.-K., Adelt S., Vogel G., Riley A.M., Potter B.V.L., Shears S.B. Curr. Biol. 12:477-482(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Inositol 1,3,4-trisphosphate 5/6-kinase associates with the COP9 signalosome by binding to CSN1." Sun Y., Wilson M.P., Majerus P.W. J. Biol. Chem. 277:45759-45764(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GPS1.
[7]	"Inositol 1,3,4-trisphosphate 5/6-kinase inhibits tumor necrosis factor-induced apoptosis." Sun Y., Mochizuki Y., Majerus P.W. J. Biol. Chem. 278:43645-43653(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"The Ins(1,3,4)P3 5/6-kinase/Ins(3,4,5,6)P4 1-kinase is not a protein kinase." Qian X., Mitchell J., Wei S.J., Williams J., Petrovich R.M., Shears S.B. Biochem. J. 389:389-395(2005) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF ARG-106; LYS-157; GLY-163; ASP-281; ASP-295 AND ASN-297.
[9]	"Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-trisphosphate 5/6-kinase." Miller G.J., Wilson M.P., Majerus P.W., Hurley J.H. Mol. Cell 18:201-212(2005) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF LYS-18; HIS-58; LYS-59; ARG-106; HIS-162; GLY-163; HIS-167; GLN-188; HIS-193; LYS-199; ARG-212; SER-214; LEU-215; ASN-297 AND GLY-301.
[10]	"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].
[11]	"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB." Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R. Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Regulation of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) by reversible lysine acetylation." Zhang C., Majerus P.W., Wilson M.P. Proc. Natl. Acad. Sci. U.S.A. 109:2290-2295(2012) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION AT LYS-340; LYS-383 AND LYS-410.
[13]	"Integration of inositol phosphate signaling pathways via human ITPK1." Chamberlain P.P., Qian X., Stiles A.R., Cho J., Jones D.H., Lesley S.A., Grabau E.A., Shears S.B., Spraggon G. J. Biol. Chem. 282:28117-28125(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-335 IN COMPLEXES WITH MANGANESE; ATP ANALOG AND ADP, FUNCTION, SUBUNIT.
[14]	"Structure of human inositol 1,3,4-trisphosphate 5/6-kinase." Structural genomics consortium (SGC) Submitted (FEB-2007) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.01 ANGSTROMS) OF 1-327.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U51336 mRNA. Translation: AAC50483.1.
AF279372 mRNA. Translation: AAG44835.1.
BC003622 mRNA. Translation: AAH03622.1.
BC007428 mRNA. Translation: AAH07428.1.
BC018192 mRNA. Translation: AAH18192.1.

RefSeq

NP_001136065.1. NM_001142593.1.
NP_001136066.1. NM_001142594.1.
NP_055031.2. NM_014216.4.

UniGene

Hs.308122.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ODT	X-ray	2.01	X	1-327	[»]
2Q7D	X-ray	1.60	A/B	1-335	[»]
2QB5	X-ray	1.80	A/B	1-335	[»]

ProteinModelPortal

Q13572.

SMR

Q13572. Positions 6-322.

ModBase

Search...

MobiDB

Search...

Protein-protein interaction databases

BioGrid

109910. 6 interactions.

DIP

DIP-60016N.

IntAct

Q13572. 2 interactions.

MINT

MINT-1463374.

STRING

9606.ENSP00000267615.

Chemistry

ChEMBL

CHEMBL1938220.

PTM databases

PhosphoSite

Q13572.

Polymorphism databases

DMDM

83288249.

Proteomic databases

PaxDb

Q13572.

PRIDE

Q13572.

Protocols and materials databases

DNASU

3705.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000267615; ENSP00000267615; ENSG00000100605. [Q13572-1]
ENST00000354313; ENSP00000346272; ENSG00000100605. [Q13572-2]
ENST00000556603; ENSP00000451091; ENSG00000100605. [Q13572-1]

GeneID

3705.

KEGG

hsa:3705.

UCSC

uc001ybe.2. human. [Q13572-2]
uc001ybf.3. human. [Q13572-1]

Organism-specific databases

CTD

3705.

GeneCards

GC14M093403.

H-InvDB

HIX0037938.

HGNC

HGNC:6177. ITPK1.

HPA

HPA055230.

MIM

601838. gene.

neXtProt

NX_Q13572.

PharmGKB

PA29974.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG85132.

HOVERGEN

HBG079462.

KO

K00913.

OMA

CSASPGC.

OrthoDB

EOG70GMG7.

PhylomeDB

Q13572.

TreeFam

TF329288.

Enzyme and pathway databases

BioCyc

MetaCyc:HS02123-MONOMER.

BRENDA

2.7.1.134. 2681.

Reactome

REACT_111217. Metabolism.
REACT_604. Hemostasis.

SABIO-RK

Q13572.

Gene expression databases

ArrayExpress

Q13572.

Bgee

Q13572.

Genevestigator

Q13572.

Family and domain databases

InterPro

IPR011761. ATP-grasp.
IPR008656. Inositol_tetrakis-P_1-kinase.
[Graphical view]

Pfam

PF05770. Ins134_P3_kin. 1 hit.
[Graphical view]

PROSITE

PS50975. ATP_GRASP. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

ITPK1. human.

EvolutionaryTrace

Q13572.

GeneWiki

ITPK1.

GenomeRNAi

3705.

NextBio

14521.

PRO

Q13572.

SOURCE

Search...

Entry information

Entry name

ITPK1_HUMAN

Accession

Primary (citable) accession number: Q13572
Secondary accession number(s): Q9BTL6, Q9H2E7

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 6, 2005
Last sequence update:	December 6, 2005
Last modified:	April 16, 2014
This is version 116 of the entry and version 2 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.