Q9BQB4 (SOST_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Sclerostin

Gene names

Name:	SOST
ORF Names:	UNQ2976/PRO7455/PRO7476

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	213 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	Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation. Ref.8
Subunit structure	Interacts with LRP4 (via the extracellular domain); the interaction facilitates the inhibition of Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains); the interaction inhibits Wnt-mediated signaling. Interacts with LRP6. Ref.8 Ref.11
Subcellular location	Secreted › extracellular space › extracellular matrix Ref.9.
Tissue specificity	Widely expressed at low levels with highest levels in bone, cartilage, kidney, liver, bone marrow and primary osteoblasts differentiated for 21 days. Detected in the subendothelial layer of the aortic intima (at protein level). Ref.9
Involvement in disease	Sclerosteosis 1 (SOST1) [MIM:269500]: An autosomal recessive sclerosing bone dysplasia characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.2 Ref.13 Van Buchem disease (VBCH) [MIM:239100]: VBCH is an autosomal recessive sclerosing bone dysplasia characterized by endosteal hyperostosis of the mandible, skull, ribs, clavicles, and diaphyses of the long bones. Affected patients present a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet. The clinical consequence of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurological pain, and, very rarely, blindness as a consequence of optic atrophy. Serum alkaline phosphatase levels are elevated. Note: The disease is caused by mutations affecting the gene represented in this entry. A 52 kb deletion downstream of SOST results in SOST transcription suppression causing van Buchem disease. Ref.7 Craniodiaphyseal dysplasia autosomal dominant (CDD) [MIM:122860]: A severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. The sclerosis is so severe that the resulting facial distortion is referred to as 'leontiasis ossea' (leonine faces) and the bone deposition results in progressive stenosis of craniofacial foramina. Respiratory obstruction due to choanal stenosis compromises the clinical outcomes of affected patients. Note: The disease is caused by mutations affecting the gene represented in this entry. Heterozygous mutations located in the secretion signal of the SOST gene prevent sclerostin secretion and can be responsible for craniodiaphyseal dysplasia. Ref.10
Sequence similarities	Belongs to the sclerostin family. Contains 1 CTCK (C-terminal cystine knot-like) domain.

Ontologies

Keywords
Biological process	Wnt signaling pathway
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Signal
Ligand	Heparin-binding
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW cellular response to parathyroid hormone stimulus Inferred from direct assay PubMed 17696759. Source: UniProtKB negative regulation of BMP signaling pathway Inferred from direct assay PubMed 14633986. Source: MGI negative regulation of Wnt receptor signaling pathway involved in dorsal/ventral axis specification Inferred from direct assay Ref.8. Source: BHF-UCL negative regulation of canonical Wnt receptor signaling pathway Inferred from direct assay Ref.8. Source: BHF-UCL negative regulation of ossification Non-traceable author statement Ref.1PubMed 17696759. Source: UniProtKB negative regulation of protein complex assembly Inferred from direct assay Ref.8. Source: BHF-UCL ossification Inferred from electronic annotation. Source: Compara positive regulation of transcription, DNA-dependent Inferred from mutant phenotype PubMed 17696759. Source: UniProtKB response to mechanical stimulus Inferred from expression pattern PubMed 21723865. Source: UniProtKB
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara extracellular space Inferred from electronic annotation. Source: Compara proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	heparin binding Inferred from electronic annotation. Source: UniProtKB-KW transcription factor binding Inferred from direct assay PubMed 17696759. Source: UniProtKB
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: Q9BQB4-1)

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: Q9BQB4-2)

The sequence of this isoform differs from the canonical sequence as follows:
     64-73: RPPHHPFETK → WPGGRPPSRAPLST

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Ref.6

Chain

24 – 213

190

Sclerostin

PRO_0000033177

Regions

Domain

82 – 172

91

CTCK

Amino acid modifications

Glycosylation

53

1

N-linked (GlcNAc...) Potential

Glycosylation

175

1

N-linked (GlcNAc...) Potential

Disulfide bond

80 ↔ 134

Ref.12

Disulfide bond

94 ↔ 148

Ref.12

Disulfide bond

105 ↔ 165

Ref.12

Disulfide bond

109 ↔ 167

Ref.12

Natural variations

Alternative sequence

64 – 73

10

RPPHHPFETK → WPGGRPPSRAPLST in isoform 2.

VSP_010189

Natural variant

21

1

V → L in CDD; affects protein secretion. Ref.10

VAR_065766

Natural variant

21

1

V → M in CDD; de novo mutation; affects protein secretion. Ref.10

VAR_065767

Natural variant

167

1

C → R in SOST1; leads to retention of the mutant protein in the endoplasmic reticulum; leads to a complete loss of function of the protein. Ref.13

VAR_063982

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

213

Helix Strand Turn

Details...

Beta strand

78 – 80

3

Beta strand

82 – 87

6

Beta strand

95 – 98

4

Beta strand

100 – 105

6

Beta strand

139 – 147

9

Beta strand

155 – 162

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 2001. Version 1. Checksum: 30DBD55CE73D5BB2	FASTA	213	24,031
	10 20 30 40 50 60 MQLPLALCLV CLLVHTAFRV VEGQGWQAFK NDATEIIPEL GEYPEPPPEL ENNKTMNRAE 70 80 90 100 110 120 NGGRPPHHPF ETKDVSEYSC RELHFTRYVT DGPCRSAKPV TELVCSGQCG PARLLPNAIG 130 140 150 160 170 180 RGKWWRPSGP DFRCIPDRYR AQRVQLLCPG GEAPRARKVR LVASCKCKRL TRFHNQSELK 190 200 210 DFGTEAARPQ KGRKPRPRAR SAKANQAELE NAY
	Isoform 2 [UniParc]. Checksum: 652294D9DE5DB402	FASTA	217	24,264
	10 20 30 40 50 60 MQLPLALCLV CLLVHTAFRV VEGQGWQAFK NDATEIIPEL GEYPEPPPEL ENNKTMNRAE 70 80 90 100 110 120 NGGWPGGRPP SRAPLSTDVS EYSCRELHFT RYVTDGPCRS AKPVTELVCS GQCGPARLLP 130 140 150 160 170 180 NAIGRGKWWR PSGPDFRCIP DRYRAQRVQL LCPGGEAPRA RKVRLVASCK CKRLTRFHNQ 190 200 210 SELKDFGTEA ARPQKGRKPR PRARSAKANQ AELENAY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)." Balemans W., Ebeling M., Patel N., van Hul E., Olson P., Dioszegi M., Lacza C., Wuyts W., van den Ende J., Willems P., Paes-Alves A.F., Hill S., Bueno M., Ramos F.J., Tacconi P., Dikkers F.G., Stratakis C., Lindpaintner K. , Vickery B., Foernzler D., Van Hul W. Hum. Mol. Genet. 10:537-543(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INVOLVEMENT IN SOST1.
[2]	"Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein." Brunkow M.E., Gardner J.C., Van Ness J., Paeper B.W., Kovacevich B.R., Proll S., Skonier J.E., Zhao L., Sabo P.J., Fu Y.H., Alisch R.S., Gillett L., Colbert T., Tacconi P., Galas D., Hamersma H., Beighton P., Mulligan J.T. Am. J. Hum. Genet. 68:577-589(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), INVOLVEMENT IN SOST1.
[3]	"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] (ISOFORMS 1 AND 2).
[4]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(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] (ISOFORM 1).
[6]	"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 24-38.
[7]	"Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease." Balemans W., Patel N., Ebeling M., Van Hul E., Wuyts W., Lacza C., Dioszegi M., Dikkers F.G., Hildering P., Willems P.J., Verheij J.B., Lindpaintner K., Vickery B., Foernzler D., Van Hul W. J. Med. Genet. 39:91-97(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN VBCH.
[8]	"SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor." Semenov M., Tamai K., He X. J. Biol. Chem. 280:26770-26775(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH LRP5 AND LRP6.
[9]	"Proteomics characterization of extracellular space components in the human aorta." Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M. Mol. Cell. Proteomics 9:2048-2062(2010) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[10]	"Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia." Kim S.J., Bieganski T., Sohn Y.B., Kozlowski K., Semenov M., Okamoto N., Kim C.H., Ko A.R., Ahn G.H., Choi Y.L., Park S.W., Ki C.S., Kim O.H., Nishimura G., Unger S., Superti-Furga A., Jin D.K. Hum. Genet. 129:497-502(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN CDD, VARIANTS CDD MET-21 AND LEU-21, CHARACTERIZATION OF VARIANTS CDD MET-21 AND LEU-21.
[11]	"Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function." Leupin O., Piters E., Halleux C., Hu S., Kramer I., Morvan F., Bouwmeester T., Schirle M., Bueno-Lozano M., Fuentes F.J., Itin P.H., Boudin E., de Freitas F., Jennes K., Brannetti B., Charara N., Ebersbach H., Geisse S. , Lu C.X., Bauer A., Van Hul W., Kneissel M. J. Biol. Chem. 286:19489-19500(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LRP4; LRP5 AND LRP6.
[12]	"Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation." Veverka V., Henry A.J., Slocombe P.M., Ventom A., Mulloy B., Muskett F.W., Muzylak M., Greenslade K., Moore A., Zhang L., Gong J., Qian X., Paszty C., Taylor R.J., Robinson M.K., Carr M.D. J. Biol. Chem. 284:10890-10900(2009) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 25-213, HEPARIN-BINDING, DISULFIDE BONDS.
[13]	"First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function." Piters E., Culha C., Moester M., Van Bezooijen R., Adriaensen D., Mueller T., Weidauer S., Jennes K., de Freitas F., Loewik C., Timmermans J.-P., Van Hul W., Papapoulos S. Hum. Mutat. 31:E1526-E1543(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SOST1 ARG-167, CHARACTERIZATION OF VARIANT SOST1 ARG-167.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF331844 mRNA. Translation: AAK16158.1.
AF326736 Genomic DNA. Translation: AAK13451.1.
AF326739 mRNA. Translation: AAK13454.1.
AY358203 mRNA. Translation: AAQ88570.1.
AY358627 mRNA. Translation: AAQ88990.1.
AC055813 Genomic DNA. No translation available.
BC101086 mRNA. Translation: AAI01087.1.
BC101087 mRNA. Translation: AAI01088.1.
BC101088 mRNA. Translation: AAI01089.1.
BC101089 mRNA. Translation: AAI01090.1.

IPI

IPI00019272.
IPI00410101.

RefSeq

NP_079513.1. NM_025237.2.

UniGene

Hs.349204.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2K8P	NMR	-	A	25-213	[»]

ProteinModelPortal

Q9BQB4.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-59407N.

IntAct

Q9BQB4. 96 interactions.

STRING

9606.ENSP00000301691.

Polymorphism databases

DMDM

20140220.

Proteomic databases

PaxDb

Q9BQB4.

PRIDE

Q9BQB4.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000301691; ENSP00000301691; ENSG00000167941.

GeneID

50964.

KEGG

hsa:50964.

UCSC

uc002iec.1. human.

Organism-specific databases

CTD

50964.

GeneCards

GC17M041841.

HGNC

HGNC:13771. SOST.

HPA

CAB025660.

MIM

122860. phenotype.
239100. phenotype.
269500. phenotype.
605740. gene.

neXtProt

NX_Q9BQB4.

Orphanet

1513. Craniodiaphyseal dysplasia.
3416. Hyperostosis corticalis generalisata.
3152. Sclerosteosis.

PharmGKB

PA37809.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG40285.

HOGENOM

HOG000252934.

HOVERGEN

HBG003729.

InParanoid

Q9BQB4.

KO

K16834.

OMA

DVSEYSC.

OrthoDB

EOG4J3WJ2.

PhylomeDB

Q9BQB4.

Gene expression databases

Bgee

Q9BQB4.

CleanEx

HS_SOST.

Genevestigator

Q9BQB4.

GermOnline

ENSG00000167941. Homo sapiens.

Family and domain databases

InterPro

IPR008835. Sclerostin/SOSTDC1.
IPR015665. SOST.
[Graphical view]

PANTHER

PTHR14903. PTHR14903. 1 hit.
PTHR14903:SF2. PTHR14903:SF2. 1 hit.

Pfam

PF05463. Sclerostin. 1 hit.
[Graphical view]

PROSITE

PS01185. CTCK_1. False negative.
PS01225. CTCK_2. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q9BQB4.

GenomeRNAi

50964.

NextBio

53429.

SOURCE

Search...

Entry information

Entry name

SOST_HUMAN

Accession

Primary (citable) accession number: Q9BQB4
Secondary accession number(s): Q495N9

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 5, 2002
Last sequence update:	June 1, 2001
Last modified:	May 1, 2013
This is version 108 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.