Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q9UIK4 (DAPK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 132. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Death-associated protein kinase 2

Short name=DAP kinase 2
EC=2.7.11.1
Alternative name(s):
DAP-kinase-related protein 1
Short name=DRP-1
Gene names
Name:DAPK2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length370 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Acts as a mediator of anoikis and a suppressor of beta-catenin-dependent anchorage-independent growth of malignant epithelial cells. May play a role in granulocytic maturation. Ref.1 Ref.2 Ref.3 Ref.6 Ref.8 Ref.10 Ref.12

Isoform 2 is not regulated by calmodulin. It can phosphorylate MYL9. It can induce membrane blebbing and autophagic cell death. Ref.1 Ref.2 Ref.3 Ref.6 Ref.8 Ref.10 Ref.12

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium. Ref.1 Ref.2 Ref.6

Enzyme regulation

Activated by Ca2+/calmodulin. Regulated by a double locking mechanism, involving autophosphorylation at Ser-318, calmodulin binding, and dimerization. In the inactive state, Ser-318 is phosphorylated, and the kinase is dimeric. Activation involves: dephosphorylation at Ser-318, release-of-autoinhibition mechanism where calmodulin binding induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain, and generation of the monomeric active form of the kinase. Ref.1

Subunit structure

Homodimer in its autoinhibited state. Active as monomer By similarity. Isoform 2 but not isoform 1 can interact with ATF4. Ref.2 Ref.6

Subcellular location

Cytoplasm. Cytoplasmic vesicleautophagosome lumen Ref.2 Ref.8.

Tissue specificity

Isoform 2 is expressed in embryonic stem cells (at protein level). Isoform 1 is ubiquitously expressed in all tissue types examined with high levels in heart, lung and skeletal muscle. It is expressed abundantly in cells differentiated toward granulocytes and low in undifferentiated, normal and leukemic hematopoietic cells and monocytes/macrophages. Ref.1 Ref.3 Ref.10

Induction

Up-regulated during granulocytic maturation. Ref.1 Ref.10

Domain

The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core By similarity.

Post-translational modification

Autophosphorylation at Ser-318 inhibits its catalytic activity. Dephosphorylated at Ser-318 in response to activated Fas and TNF-alpha receptors. Ref.6

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
   Cellular componentCytoplasm
Cytoplasmic vesicle
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandATP-binding
Calmodulin-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processanoikis

Inferred from mutant phenotype Ref.12. Source: UniProtKB

apoptotic process

Traceable author statement Ref.2. Source: UniProtKB

intracellular signal transduction

Inferred from direct assay Ref.1. Source: UniProtKB

protein autophosphorylation

Traceable author statement Ref.9. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.1. Source: UniProtKB

regulation of apoptotic process

Traceable author statement Ref.9. Source: UniProtKB

regulation of autophagy

Traceable author statement Ref.9. Source: UniProtKB

regulation of intrinsic apoptotic signaling pathway

Inferred from mutant phenotype Ref.1. Source: UniProtKB

   Cellular_componentautophagic vacuole lumen

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoplasm

Inferred from direct assay Ref.1Ref.2. Source: UniProtKB

cytoplasmic vesicle

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from direct assay Ref.1. Source: UniProtKB

calmodulin binding

Inferred from direct assay Ref.1. Source: UniProtKB

identical protein binding

Inferred from physical interaction Ref.2Ref.6. Source: IntAct

protein serine/threonine kinase activity

Traceable author statement Ref.9. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

itself4EBI-77154,EBI-77154

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9UIK4-1)

Also known as: Alpha;

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: Q9UIK4-2)

Also known as: Beta;

The sequence of this isoform differs from the canonical sequence as follows:
     287-370: PVDNQQAMVR...LHPRRRSSTS → SKGEGRAPEQ...TEEFLAGWKL
Note: Contains a leucine zipper at positions 434-451.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 370370Death-associated protein kinase 2
PRO_0000085912

Regions

Domain23 – 285263Protein kinase
Nucleotide binding29 – 379ATP By similarity UniProtKB P53355
Region277 – 34468Calmodulin-binding Ref.1
Region292 – 30110Autoinhibitory domain By similarity

Sites

Active site1491Proton acceptor By similarity UniProtKB P53355
Binding site521ATP Ref.1 Ref.2

Amino acid modifications

Modified residue2991Phosphoserine By similarity
Modified residue3181Phosphoserine; by autocatalysis Ref.6
Modified residue3491Phosphoserine Ref.11

Natural variations

Alternative sequence287 – 37084PVDNQ…RSSTS → SKGEGRAPEQRKTEPTQLKT KHLREYTLKCHSSMPPNNSY VNFERFACVVEDVARVDLGC RALVEAHDTIQDDVEALVSI FNEKEAWYREENESARHDLS QLRYEFRKVESLKKLLREDI QATGCSLGSMARKLDHLQAQ FEILRQELSADLQWIQELVG SFQLESGSSEGLGSTFYQDT SESLSELLSRSCTEEFLAGW KL in isoform 2.
VSP_042057
Natural variant601R → W. Ref.13
Corresponds to variant rs56047843 [ dbSNP | Ensembl ].
VAR_040436
Natural variant2711R → W. Ref.13
Corresponds to variant rs34270163 [ dbSNP | Ensembl ].
VAR_040437

Experimental info

Mutagenesis521K → A: Loss of activity, apoptotic function and of autophosphorylation. Ref.1 Ref.2 Ref.6
Mutagenesis299 – 33032Missing: Loss of ca(2+)-calmodulin binding, increase in activity, loss of autophosphorylation. Ref.1 Ref.6
Mutagenesis2991S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.6
Mutagenesis3181S → A: Loss of Ca(2+)-calmodulin independent phosphorylation, increase in apoptotic activity. Ref.6
Mutagenesis3181S → D: Abolishes apoptotic activity. Ref.6
Mutagenesis3201S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.6
Mutagenesis3231S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.6
Mutagenesis3291T → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.6
Sequence conflict2411A → S in AAC35001. Ref.2
Sequence conflict2531Q → H in AAC35001. Ref.2

Secondary structure

........................................................ 370
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Alpha) [UniParc].

Last modified May 1, 2000. Version 1.
Checksum: 035E914BBCD881A2

FASTA37042,898
        10         20         30         40         50         60 
MFQASMRSPN MEPFKQQKVE DFYDIGEELG SGQFAIVKKC REKSTGLEYA AKFIKKRQSR 

        70         80         90        100        110        120 
ASRRGVSREE IEREVSILRQ VLHHNVITLH DVYENRTDVV LILELVSGGE LFDFLAQKES 

       130        140        150        160        170        180 
LSEEEATSFI KQILDGVNYL HTKKIAHFDL KPENIMLLDK NIPIPHIKLI DFGLAHEIED 

       190        200        210        220        230        240 
GVEFKNIFGT PEFVAPEIVN YEPLGLEADM WSIGVITYIL LSGASPFLGD TKQETLANIT 

       250        260        270        280        290        300 
AVSYDFDEEF FSQTSELAKD FIRKLLVKET RKRLTIQEAL RHPWITPVDN QQAMVRRESV 

       310        320        330        340        350        360 
VNLENFRKQY VRRRWKLSFS IVSLCNHLTR SLMKKVHLRP DEDLRNCESD TEEDIARRKA 

       370 
LHPRRRSSTS 

« Hide

Isoform 2 (Beta) [UniParc].

Checksum: 34F716A709C569B8
Show »

FASTA48855,931

References

« Hide 'large scale' references
[1]"Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity."
Kawai T., Nomura F., Hoshino K., Copeland N.G., Gilbert D.J., Jenkins N.A., Akira S.
Oncogene 18:3471-3480(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME REGULATION, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-52.
Tissue: Skeletal muscle.
[2]"Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis."
Inbal B., Shani G., Cohen O., Kissil J.L., Kimchi A.
Mol. Cell. Biol. 20:1044-1054(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, HOMODIMERIZATION, MUTAGENESIS OF LYS-52.
Tissue: Kidney.
[3]"New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform."
Shoval Y., Berissi H., Kimchi A., Pietrokovski S.
PLoS ONE 6:E17344-E17344(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION (ISOFORM 2), TISSUE SPECIFICITY, INTERACTION WITH ATF4 (ISOFORM 2).
[4]"Analysis of the DNA sequence and duplication history of human chromosome 15."
Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A. expand/collapse author list , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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].
[6]"Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding."
Shani G., Henis-Korenblit S., Jona G., Gileadi O., Eisenstein M., Ziv T., Admon A., Kimchi A.
EMBO J. 20:1099-1113(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, HOMODIMERIZATION, MUTAGENESIS OF LYS-52; SER-299; SER-318; SER-320; SER-323 AND THR-329, PHOSPHORYLATION AT SER-318.
[7]"The DAP-kinase family of proteins: study of a novel group of calcium-regulated death-promoting kinases."
Shohat G., Shani G., Eisenstein M., Kimchi A.
Biochim. Biophys. Acta 1600:45-50(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[8]"DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death."
Inbal B., Bialik S., Sabanay I., Shani G., Kimchi A.
J. Cell Biol. 157:455-468(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]"The death-associated protein kinases: structure, function, and beyond."
Bialik S., Kimchi A.
Annu. Rev. Biochem. 75:189-210(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[10]"The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells."
Rizzi M., Tschan M.P., Britschgi C., Britschgi A., Huegli B., Grob T.J., Leupin N., Mueller B.U., Simon H.U., Ziemiecki A., Torbett B.E., Fey M.F., Tobler A.
J. Leukoc. Biol. 81:1599-1608(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION, TISSUE SPECIFICITY.
[11]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-349, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"Down-regulation of death-associated protein kinase-2 is required for beta-catenin-induced anoikis resistance of malignant epithelial cells."
Li H., Ray G., Yoo B.H., Erdogan M., Rosen K.V.
J. Biol. Chem. 284:2012-2022(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[13]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] TRP-60 AND TRP-271.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB018001 mRNA. Translation: BAA88063.1.
AF052941 mRNA. Translation: AAC35001.1.
GU056176 mRNA. Translation: ADD83109.1.
AC015914 Genomic DNA. No translation available.
AC021541 Genomic DNA. No translation available.
BC114506 mRNA. Translation: AAI14507.1.
RefSeqNP_055141.2. NM_014326.3.
XP_005254323.1. XM_005254266.2.
UniGeneHs.237886.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1WMKX-ray3.60A/B/C/D/E/F/G/H11-330[»]
1WRZX-ray2.00B312-330[»]
1Z9XX-ray3.93A/B/C11-330[»]
1ZUZX-ray1.91B312-330[»]
1ZWSX-ray2.90A/B/C/D/E/F/G/H11-297[»]
2A27X-ray3.00A/B/C/D/E/F/G/H11-330[»]
2A2AX-ray1.47A/B/C/D11-330[»]
2CKEX-ray2.80A/B/C/D11-330[»]
ProteinModelPortalQ9UIK4.
SMRQ9UIK4. Positions 12-315.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid117137. 2 interactions.
STRING9606.ENSP00000261891.

Chemistry

BindingDBQ9UIK4.
ChEMBLCHEMBL3123.
GuidetoPHARMACOLOGY2003.

PTM databases

PhosphoSiteQ9UIK4.

Polymorphism databases

DMDM38605084.

Proteomic databases

PaxDbQ9UIK4.
PRIDEQ9UIK4.

Protocols and materials databases

DNASU23604.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000261891; ENSP00000261891; ENSG00000035664. [Q9UIK4-1]
ENST00000457488; ENSP00000408277; ENSG00000035664. [Q9UIK4-1]
ENST00000558069; ENSP00000453235; ENSG00000035664. [Q9UIK4-2]
GeneID23604.
KEGGhsa:23604.
UCSCuc002amr.3. human. [Q9UIK4-1]

Organism-specific databases

CTD23604.
GeneCardsGC15M064199.
HGNCHGNC:2675. DAPK2.
neXtProtNX_Q9UIK4.
PharmGKBPA27143.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233016.
HOVERGENHBG100551.
InParanoidQ9UIK4.
KOK08803.
OMAYARRRWK.
PhylomeDBQ9UIK4.
TreeFamTF314166.

Enzyme and pathway databases

ReactomeREACT_578. Apoptosis.
SignaLinkQ9UIK4.

Gene expression databases

ArrayExpressQ9UIK4.
BgeeQ9UIK4.
CleanExHS_DAPK2.
GenevestigatorQ9UIK4.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR020675. Myosin_light_ch_kinase-rel.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERPTHR22964. PTHR22964. 1 hit.
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 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

ChiTaRSDAPK2. human.
EvolutionaryTraceQ9UIK4.
GeneWikiDAPK2.
GenomeRNAi23604.
NextBio35500973.
PROQ9UIK4.

Entry information

Entry nameDAPK2_HUMAN
AccessionPrimary (citable) accession number: Q9UIK4
Secondary accession number(s): E9JGM7, O75892, Q24JS1
Entry history
Integrated into UniProtKB/Swiss-Prot: November 28, 2003
Last sequence update: May 1, 2000
Last modified: April 16, 2014
This is version 132 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

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM