O94907 (DKK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dickkopf-related protein 1
Short name=Dickkopf-1
Short name=Dkk-1
Short name=hDkk-1

Alternative name(s):
SK

Gene names

Name:	DKK1
ORF Names:	UNQ492/PRO1008

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	266 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease. Ref.15
Subunit structure	Interacts with LRP6. Interacts (via the C-termianl Cys-rich domain) with LRP5 (via beta-propeller regions 3 and 4); the interaction, enhanced by MESD and or KREMEN, antagonizes Wnt-mediated signaling. Ref.10 Ref.12 Ref.13
Subcellular location	Secreted.
Tissue specificity	Placenta.
Domain	The C-terminal cysteine-rich domain mediates interaction with LRP5 and LRP6 By similarity.
Sequence similarities	Belongs to the dickkopf family.

Ontologies

Keywords
Biological process	Wnt signaling pathway
Cellular component	Secreted
Domain	Signal
Molecular function	Developmental protein
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway involved in somitogenesis Inferred from electronic annotation. Source: Compara cell morphogenesis involved in differentiation Inferred from electronic annotation. Source: Compara embryonic limb morphogenesis Inferred from electronic annotation. Source: Compara endoderm formation Inferred from electronic annotation. Source: Compara face morphogenesis Inferred from electronic annotation. Source: Compara forebrain development Inferred from electronic annotation. Source: Compara hair follicle development Inferred from electronic annotation. Source: Compara mesoderm formation Inferred from electronic annotation. Source: Compara negative regulation of BMP signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of canonical Wnt receptor signaling pathway involved in cardiac muscle cell fate commitment Inferred from direct assay PubMed 20559569. Source: BHF-UCL negative regulation of cardiac muscle cell differentiation Inferred from direct assay PubMed 20559569. Source: BHF-UCL negative regulation of mesodermal cell fate specification Inferred from direct assay PubMed 20559569. Source: BHF-UCL negative regulation of pathway-restricted SMAD protein phosphorylation Inferred from direct assay PubMed 20559569. Source: BHF-UCL negative regulation of peptidyl-serine phosphorylation Inferred from direct assay PubMed 20723538. Source: BHF-UCL negative regulation of protein complex assembly Inferred from direct assay Ref.10. Source: BHF-UCL negative regulation of skeletal muscle tissue development Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 20723538. Source: BHF-UCL positive regulation of heart induction by negative regulation of canonical Wnt receptor signaling pathway Inferred from sequence or structural similarity. Source: BHF-UCL regulation of endodermal cell fate specification Inferred from direct assay PubMed 20559569. Source: BHF-UCL regulation of receptor internalization Inferred from direct assay PubMed 17804805. Source: BHF-UCL response to retinoic acid Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular space Inferred from direct assay Ref.10PubMed 11742004. Source: BHF-UCL plasma membrane Inferred from direct assay PubMed 16263759. Source: MGI
Molecular_function	growth factor activity Traceable author statement Ref.1. Source: ProtInc low-density lipoprotein particle receptor binding Inferred from direct assay PubMed 16263759. Source: MGI receptor antagonist activity Inferred from direct assay PubMed 20723538. Source: BHF-UCL signal transducer activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MDFI	Q99750	3	EBI-742864,EBI-724076

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 31

31

Ref.9

Chain

32 – 266

235

Dickkopf-related protein 1

PRO_0000007218

Regions

Region

85 – 138

54

DKK-type Cys-1

Region

189 – 263

75

DKK-type Cys-2

Amino acid modifications

Glycosylation

61

1

O-linked (GalNAc...) Ref.14

Glycosylation

256

1

N-linked (GlcNAc...) Ref.14

Disulfide bond

85 ↔ 97

Ref.14 Ref.15

Disulfide bond

91 ↔ 111

Ref.14 Ref.15

Disulfide bond

114 ↔ 128

Ref.14 Ref.15

Disulfide bond

121 ↔ 133

Ref.14 Ref.15

Disulfide bond

127 ↔ 138

Ref.14 Ref.15

Disulfide bond

189 ↔ 201

Ref.14 Ref.15

Disulfide bond

195 ↔ 210

Ref.14 Ref.15

Disulfide bond

200 ↔ 237

Ref.14 Ref.15

Disulfide bond

220 ↔ 245

Ref.14 Ref.15

Disulfide bond

239 ↔ 263

Ref.14 Ref.15

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

266

Helix Strand Turn

Details...

Helix

192 – 194

3

Beta strand

199 – 204

6

Beta strand

207 – 212

6

Helix

226 – 231

6

Beta strand

243 – 247

5

Beta strand

261 – 265

5

Sequences

	Sequence		Length	Mass (Da)
	O94907 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: 5E878B2CCE4236BA	FASTA	266	28,672
	10 20 30 40 50 60 MMALGAAGAT RVFVAMVAAA LGGHPLLGVS ATLNSVLNSN AIKNLPPPLG GAAGHPGSAV 70 80 90 100 110 120 SAAPGILYPG GNKYQTIDNY QPYPCAEDEE CGTDEYCASP TRGGDAGVQI CLACRKRRKR 130 140 150 160 170 180 CMRHAMCCPG NYCKNGICVS SDQNHFRGEI EETITESFGN DHSTLDGYSR RTTLSSKMYH 190 200 210 220 230 240 TKGQEGSVCL RSSDCASGLC CARHFWSKIC KPVLKEGQVC TKHRRKGSHG LEIFQRCYCG 250 260 EGLSCRIQKD HHQASNSSRL HTCQRH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling." Fedi P., Bafico A., Nieto Soria A., Burgess W.H., Miki T., Bottaro D.P., Kraus M.H., Aaronson S.A. J. Biol. Chem. 274:19465-19472(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Leiomyosarcoma.
[2]	"Functional and structural diversity of the human Dickkopf gene family." Krupnik V.E., Sharp J.D., Jiang C., Robison K., Chickering T.W., Amaravadi L., Brown D.E., Guyot D., Mays G., Leiby K., Chang B., Duong T., Goodearl A.D.J., Gearing D.P., Sokol S.Y., McCarthy S.A. Gene 238:301-313(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal kidney.
[3]	Tate G., Suzuki T., Mitsuya T. Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly." Roessler E., Du Y., Glinka A., Dutra A., Niehrs C., Muenke M. Cytogenet. Cell Genet. 89:220-224(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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.
[9]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 32-46.
[10]	"Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6." Semenov M.V., Tamai K., Brott B.K., Kuhl M., Sokol S., He X. Curr. Biol. 11:951-961(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LRP6.
[11]	"Function and biological roles of the Dickkopf family of Wnt modulators." Niehrs C. Oncogene 25:7469-7481(2006) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW OF THE DKK FAMILY.
[12]	"A cell-based Dkk1 binding assay reveals roles for extracellular domains of LRP5 in Dkk1 interaction and highlights differences between wild-type and the high bone mass mutant LRP5(G171V)." Murrills R.J., Matteo J.J., Bhat B.M., Coleburn V.E., Allen K.M., Chen W., Damagnez V., Bhat R.A., Bex F.J., Bodine P.V. J. Cell. Biochem. 108:1066-1075(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LRP5.
[13]	"Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6." Bourhis E., Tam C., Franke Y., Bazan J.F., Ernst J., Hwang J., Costa M., Cochran A.G., Hannoush R.N. J. Biol. Chem. 285:9172-9179(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LRP6.
[14]	"Human Dickkopf-1 (huDKK1) protein: characterization of glycosylation and determination of disulfide linkages in the two cysteine-rich domains." Haniu M., Horan T., Spahr C., Hui J., Fan W., Chen C., Richards W.G., Lu H.S. Protein Sci. 20:1802-1813(2011) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT SER-61 AND ASN-256, DISULFIDE BONDS.
[15]	"Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6." Ahn V.E., Chu M.L., Choi H.J., Tran D., Abo A., Weis W.I. Dev. Cell 21:862-873(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 178-266 IN COMPLEX WITH LRP6, FUNCTION, DISULFIDE BONDS.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF127563 mRNA. Translation: AAD21087.1.
AF177394 mRNA. Translation: AAF02674.1.
AB020315 Genomic DNA. Translation: BAA34651.1.
AF261158, AF261157 Genomic DNA. Translation: AAG15544.1.
AY359005 mRNA. Translation: AAQ89364.1.
AK314902 mRNA. Translation: BAG37416.1.
CH471083 Genomic DNA. Translation: EAW54144.1.
BC001539 mRNA. Translation: AAH01539.1.

IPI

IPI00016353.

RefSeq

NP_036374.1. NM_012242.2.

UniGene

Hs.40499.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3S2K	X-ray	2.80	C	178-266	[»]
3S8V	X-ray	3.10	X	183-266	[»]

ProteinModelPortal

O94907.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-46461N.

IntAct

O94907. 2 interactions.

MINT

MINT-1196808.

STRING

9606.ENSP00000363081.

Proteomic databases

PaxDb

O94907.

PRIDE

O94907.

Protocols and materials databases

DNASU

22943.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000373970; ENSP00000363081; ENSG00000107984.

GeneID

22943.

KEGG

hsa:22943.

UCSC

uc001jjr.3. human.

Organism-specific databases

CTD

22943.

GeneCards

GC10P054074.

HGNC

HGNC:2891. DKK1.

HPA

CAB009726.
HPA018995.

MIM

605189. gene.

neXtProt

NX_O94907.

PharmGKB

PA27345.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG289067.

HOGENOM

HOG000246998.

HOVERGEN

HBG000441.

InParanoid

O94907.

KO

K02165.

OMA

GSVCLRS.

OrthoDB

EOG4DFPP7.

PhylomeDB

O94907.

Enzyme and pathway databases

Pathway_Interaction_DB

wnt_canonical_pathway. Canonical Wnt signaling pathway.
ps1pathway. Presenilin action in Notch and Wnt signaling.

Gene expression databases

ArrayExpress

O94907.

Bgee

O94907.

CleanEx

HS_DKK1.

Genevestigator

O94907.

GermOnline

ENSG00000107984. Homo sapiens.

Family and domain databases

InterPro

IPR006796. Dickkopf_N.
[Graphical view]

Pfam

PF04706. Dickkopf_N. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

O94907.

ChEMBL

CHEMBL6024.

ChiTaRS

DKK1. human.

GenomeRNAi

22943.

NextBio

43697.

PMAP-CutDB

O94907.

SOURCE

Search...

Entry information

Entry name

DKK1_HUMAN

Accession

Primary (citable) accession number: O94907
Secondary accession number(s): B2RC19

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 21, 2001
Last sequence update:	May 1, 1999
Last modified:	May 1, 2013
This is version 115 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.