Q9UIK4 (DAPK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

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	370 AA.
Sequence status	Complete.
Protein existence	Evidence 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.4 Ref.6 Ref.8 Ref.10 Ref.11 Isoform 2 can phosphorylate MYL9. It can induce membrane blebbing and autophagic cell death. Ref.1 Ref.2 Ref.4 Ref.6 Ref.8 Ref.10 Ref.11
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium. Ref.1 Ref.2 Ref.4
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.4
Subcellular location	Cytoplasm. Cytoplasmic vesicle › autophagosome lumen Ref.2 Ref.6.
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.8 Ref.11
Induction	Up-regulated during granulocytic maturation. Ref.1 Ref.8
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.4
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 process	Apoptosis
Cellular component	Cytoplasm Cytoplasmic vesicle
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Calmodulin-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	anoikis Inferred from mutant phenotype Ref.10. Source: UniProtKB induction of apoptosis Inferred from mutant phenotype Ref.1. Source: UniProtKB intracellular protein kinase cascade Inferred from direct assay Ref.1. Source: UniProtKB protein autophosphorylation Traceable author statement Ref.7. Source: UniProtKB regulation of autophagy Traceable author statement Ref.7. Source: UniProtKB
Cellular_component	autophagic vacuole lumen Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasm Inferred from direct assay Ref.1. Source: UniProtKB cytoplasmic vesicle Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP binding Inferred from direct assay Ref.1. Source: UniProtKB calmodulin binding Inferred from direct assay Ref.1. Source: UniProtKB calmodulin-dependent protein kinase activity Traceable author statement Ref.2. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		4	EBI-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:
     286-370: TPVDNQQAMV...LHPRRRSSTS → SKGEGRAPEQ...TEEFLAGWKL

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 370

370

Death-associated protein kinase 2

PRO_0000085912

Regions

Domain

23 – 285

263

Protein kinase

Nucleotide binding

29 – 37

9

ATP By similarity UniProtKB P53355

Region

277 – 344

68

Calmodulin-binding Ref.1

Region

292 – 301

10

Autoinhibitory domain By similarity

Sites

Active site

149

1

Proton acceptor By similarity UniProtKB P53355

Binding site

52

1

ATP Ref.1 Ref.2

Amino acid modifications

Modified residue

299

1

Phosphoserine By similarity

Modified residue

318

1

Phosphoserine; by autocatalysis Ref.4

Modified residue

349

1

Phosphoserine Ref.9

Natural variations

Alternative sequence

286 – 370

85

TPVDN…RSSTS → SKGEGRAPEQRKTEPTQLKT KHLREYTLKCHSSMPPNNSY VNFERFACVVEDVARVDLGC RALVEAHDTIQDDVEALVSI FNEKEAWYREENESARHDLS QLRYEFRKVESLKKLLREDI QATGCSLGSMARKLDHLQAQ FEILRQELSADLQWIQELVG SFQLESGSSEGLGSTFYQDT SESLSELLSRSCTEEFLAGW KL in isoform 2.

VSP_042057

Natural variant

60

1

R → W. Ref.12
Corresponds to variant rs56047843 [ dbSNP | Ensembl ].

VAR_040436

Natural variant

271

1

R → W. Ref.12
Corresponds to variant rs34270163 [ dbSNP | Ensembl ].

VAR_040437

Experimental info

Mutagenesis

52

1

K → A: Loss of activity, apoptotic function and of autophosphorylation. Ref.1 Ref.2 Ref.4

Mutagenesis

299 – 330

32

Missing: Loss of ca(2+)-calmodulin binding, increase in activity, loss of autophosphorylation. Ref.1 Ref.4

Mutagenesis

299

1

S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.4

Mutagenesis

318

1

S → A: Loss of Ca(2+)-calmodulin independent phosphorylation, increase in apoptotic activity. Ref.4

Mutagenesis

318

1

S → D: Abolishes apoptotic activity. Ref.4

Mutagenesis

320

1

S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.4

Mutagenesis

323

1

S → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.4

Mutagenesis

329

1

T → A: No effect on Ca(2+)-calmodulin independent phosphorylation or apoptotic activity. Ref.4

Sequence conflict

241

1

A → S in AAC35001. Ref.2

Sequence conflict

253

1

Q → H in AAC35001. Ref.2

Secondary structure

1

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370

Helix Strand Turn

Details...

Helix

19 – 22

4

Beta strand

23 – 31

9

Beta strand

33 – 42

10

Turn

43 – 45

3

Beta strand

48 – 56

9

Beta strand

58 – 61

4

Beta strand

63 – 66

4

Helix

68 – 80

13

Beta strand

89 – 94

6

Beta strand

96 – 103

8

Helix

111 – 116

6

Helix

123 – 142

20

Beta strand

144 – 146

3

Helix

152 – 154

3

Beta strand

155 – 158

4

Beta strand

162 – 164

3

Beta strand

167 – 169

3

Helix

191 – 193

3

Helix

196 – 199

4

Helix

207 – 222

16

Helix

232 – 240

9

Helix

248 – 251

4

Helix

256 – 263

8

Turn

270 – 272

3

Helix

276 – 281

6

Turn

283 – 285

3

Helix

290 – 298

9

Helix

303 – 312

10

Helix

314 – 328

15

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Alpha) [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 035E914BBCD881A2	FASTA	370	42,898
	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
	Isoform 2 (Beta) [UniParc]. Checksum: 044DCC4A92C549D4	FASTA	487	55,830
	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 RHPWISKGEG RAPEQRKTEP 310 320 330 340 350 360 TQLKTKHLRE YTLKCHSSMP PNNSYVNFER FACVVEDVAR VDLGCRALVE AHDTIQDDVE 370 380 390 400 410 420 ALVSIFNEKE AWYREENESA RHDLSQLRYE FRKVESLKKL LREDIQATGC SLGSMARKLD 430 440 450 460 470 480 HLQAQFEILR QELSADLQWI QELVGSFQLE SGSSEGLGST FYQDTSESLS ELLSRSCTEE FLAGWKL

References

	« Hide 'large scale' referencesShow '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]	"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].
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.
[9]	"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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"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.
[11]	"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: ALTERNATIVE SPLICING (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH ATF4.
[12]	"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. , 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.
BC114506 mRNA. Translation: AAI14507.1.

IPI

IPI00033388.

RefSeq

NP_055141.2. NM_014326.3.

UniGene

Hs.237886.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1WMK	X-ray	3.60	A/B/C/D/E/F/G/H	11-330	[»]
1WRZ	X-ray	2.00	B	312-330	[»]
1Z9X	X-ray	3.93	A/B/C	11-330	[»]
1ZUZ	X-ray	1.91	B	312-330	[»]
1ZWS	X-ray	2.90	A/B/C/D/E/F/G/H	11-297	[»]
2A27	X-ray	3.00	A/B/C/D/E/F/G/H	11-330	[»]
2A2A	X-ray	1.47	A/B/C/D	11-330	[»]
2CKE	X-ray	2.80	A/B/C/D	11-330	[»]

ProteinModelPortal

Q9UIK4.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000261891.

PTM databases

PhosphoSite

Q9UIK4.

Polymorphism databases

DMDM

38605084.

Proteomic databases

PaxDb

Q9UIK4.

PRIDE

Q9UIK4.

Protocols and materials databases

DNASU

23604.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000261891; ENSP00000261891; ENSG00000035664.
ENST00000457488; ENSP00000408277; ENSG00000035664.

GeneID

23604.

KEGG

hsa:23604.

UCSC

uc002amr.3. human.

Organism-specific databases

CTD

23604.

GeneCards

GC15M064199.

HGNC

HGNC:2675. DAPK2.

neXtProt

NX_Q9UIK4.

PharmGKB

PA27143.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233016.

HOVERGEN

HBG100551.

InParanoid

Q9UIK4.

KO

K08803.

OMA

YARRRWK.

OrthoDB

EOG4894MS.

Enzyme and pathway databases

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

Q9UIK4.

Bgee

Q9UIK4.

CleanEx

HS_DAPK2.

Genevestigator

Q9UIK4.

GermOnline

ENSG00000035664. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR020675. Myosin_light_ch_kinase-rel.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

PANTHER

PTHR22964. PTHR22964. 1 hit.

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

BindingDB

Q9UIK4.

ChEMBL

CHEMBL3123.

ChiTaRS

DAPK2. human.

EvolutionaryTrace

Q9UIK4.

GenomeRNAi

23604.

NextBio

46296.

Entry information

Entry name

DAPK2_HUMAN

Accession

Primary (citable) accession number: Q9UIK4
Secondary accession number(s): O75892, Q24JS1

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 28, 2003
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 122 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.