ID SOST_HUMAN Reviewed; 213 AA. AC Q9BQB4; Q495N9; DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 07-JAN-2015, entry version 122. DE RecName: Full=Sclerostin; DE Flags: Precursor; GN Name=SOST; ORFNames=UNQ2976/PRO7455/PRO7476; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INVOLVEMENT IN SOST1. RX PubMed=11181578; DOI=10.1093/hmg/10.5.537; RA Balemans W., Ebeling M., Patel N., van Hul E., Olson P., Dioszegi M., RA Lacza C., Wuyts W., van den Ende J., Willems P., Paes-Alves A.F., RA Hill S., Bueno M., Ramos F.J., Tacconi P., Dikkers F.G., Stratakis C., RA Lindpaintner K., Vickery B., Foernzler D., Van Hul W.; RT "Increased bone density in sclerosteosis is due to the deficiency of a RT novel secreted protein (SOST)."; RL Hum. Mol. Genet. 10:537-543(2001). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND INVOLVEMENT RP IN SOST1. RX PubMed=11179006; DOI=10.1086/318811; RA Brunkow M.E., Gardner J.C., Van Ness J., Paeper B.W., Kovacevich B.R., RA Proll S., Skonier J.E., Zhao L., Sabo P.J., Fu Y.H., Alisch R.S., RA Gillett L., Colbert T., Tacconi P., Galas D., Hamersma H., RA Beighton P., Mulligan J.T.; RT "Bone dysplasia sclerosteosis results from loss of the SOST gene RT product, a novel cystine knot-containing protein."; RL Am. J. Hum. Genet. 68:577-589(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., RA Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale RT effort to identify novel human secreted and transmembrane proteins: a RT bioinformatics assessment."; RL Genome Res. 13:2265-2270(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in RT the human lineage."; RL Nature 440:1045-1049(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 24-38. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [7] RP INVOLVEMENT IN VBCH. RX PubMed=11836356; DOI=10.1136/jmg.39.2.91; RA Balemans W., Patel N., Ebeling M., Van Hul E., Wuyts W., Lacza C., RA Dioszegi M., Dikkers F.G., Hildering P., Willems P.J., Verheij J.B., RA Lindpaintner K., Vickery B., Foernzler D., Van Hul W.; RT "Identification of a 52 kb deletion downstream of the SOST gene in RT patients with van Buchem disease."; RL J. Med. Genet. 39:91-97(2002). RN [8] RP FUNCTION, AND INTERACTION WITH LRP5 AND LRP6. RX PubMed=15908424; DOI=10.1074/jbc.M504308200; RA Semenov M., Tamai K., He X.; RT "SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor."; RL J. Biol. Chem. 280:26770-26775(2005). RN [9] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=20551380; DOI=10.1074/mcp.M110.001693; RA Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.; RT "Proteomics characterization of extracellular space components in the RT human aorta."; RL Mol. Cell. Proteomics 9:2048-2062(2010). RN [10] RP INVOLVEMENT IN CDD, VARIANTS CDD MET-21 AND LEU-21, AND RP CHARACTERIZATION OF VARIANTS CDD MET-21 AND LEU-21. RX PubMed=21221996; DOI=10.1007/s00439-011-0947-3; RA Kim S.J., Bieganski T., Sohn Y.B., Kozlowski K., Semenov M., RA Okamoto N., Kim C.H., Ko A.R., Ahn G.H., Choi Y.L., Park S.W., RA Ki C.S., Kim O.H., Nishimura G., Unger S., Superti-Furga A., Jin D.K.; RT "Identification of signal peptide domain SOST mutations in autosomal RT dominant craniodiaphyseal dysplasia."; RL Hum. Genet. 129:497-502(2011). RN [11] RP INTERACTION WITH LRP4; LRP5 AND LRP6. RX PubMed=21471202; DOI=10.1074/jbc.M110.190330; RA Leupin O., Piters E., Halleux C., Hu S., Kramer I., Morvan F., RA Bouwmeester T., Schirle M., Bueno-Lozano M., Fuentes F.J., Itin P.H., RA Boudin E., de Freitas F., Jennes K., Brannetti B., Charara N., RA Ebersbach H., Geisse S., Lu C.X., Bauer A., Van Hul W., Kneissel M.; RT "Bone overgrowth-associated mutations in the LRP4 gene impair RT sclerostin facilitator function."; RL J. Biol. Chem. 286:19489-19500(2011). RN [12] RP STRUCTURE BY NMR OF 25-213, HEPARIN-BINDING, AND DISULFIDE BONDS. RX PubMed=19208630; DOI=10.1074/jbc.M807994200; RA Veverka V., Henry A.J., Slocombe P.M., Ventom A., Mulloy B., RA Muskett F.W., Muzylak M., Greenslade K., Moore A., Zhang L., Gong J., RA Qian X., Paszty C., Taylor R.J., Robinson M.K., Carr M.D.; RT "Characterization of the structural features and interactions of RT sclerostin: molecular insight into a key regulator of Wnt-mediated RT bone formation."; RL J. Biol. Chem. 284:10890-10900(2009). RN [13] RP VARIANT SOST1 ARG-167, AND CHARACTERIZATION OF VARIANT SOST1 ARG-167. RX PubMed=20583295; DOI=10.1002/humu.21274; RA Piters E., Culha C., Moester M., Van Bezooijen R., Adriaensen D., RA Mueller T., Weidauer S., Jennes K., de Freitas F., Loewik C., RA Timmermans J.-P., Van Hul W., Papapoulos S.; RT "First missense mutation in the SOST gene causing sclerosteosis by RT loss of sclerostin function."; RL Hum. Mutat. 31:E1526-E1543(2010). CC -!- FUNCTION: Negative regulator of bone growth that acts through CC inhibition of Wnt signaling and bone formation. CC {ECO:0000269|PubMed:15908424}. CC -!- SUBUNIT: Interacts with LRP4 (via the extracellular domain); the CC interaction facilitates the inhibition of Wnt signaling. Interacts CC with LRP5 (via the first two YWTD-EGF repeat domains); the CC interaction inhibits Wnt-mediated signaling. Interacts with LRP6. CC {ECO:0000269|PubMed:15908424, ECO:0000269|PubMed:21471202}. CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular CC matrix {ECO:0000269|PubMed:20551380}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9BQB4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BQB4-2; Sequence=VSP_010189; CC Note=No experimental confirmation available.; CC -!- TISSUE SPECIFICITY: Widely expressed at low levels with highest CC levels in bone, cartilage, kidney, liver, bone marrow and primary CC osteoblasts differentiated for 21 days. Detected in the CC subendothelial layer of the aortic intima (at protein level). CC {ECO:0000269|PubMed:20551380}. CC -!- DISEASE: Sclerosteosis 1 (SOST1) [MIM:269500]: An autosomal CC recessive sclerosing bone dysplasia characterized by a generalized CC hyperostosis and sclerosis leading to a markedly thickened skull, CC with mandible, ribs, clavicles and all long bones also being CC affected. Due to narrowing of the foramina of the cranial nerves, CC facial nerve palsy, hearing loss and atrophy of the optic nerves CC can occur. Sclerosteosis is clinically and radiologically very CC similar to van Buchem disease, mainly differentiated by hand CC malformations and a large stature in sclerosteosis patients. CC {ECO:0000269|PubMed:11179006, ECO:0000269|PubMed:11181578, CC ECO:0000269|PubMed:20583295}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Van Buchem disease (VBCH) [MIM:239100]: VBCH is an CC autosomal recessive sclerosing bone dysplasia characterized by CC endosteal hyperostosis of the mandible, skull, ribs, clavicles, CC and diaphyses of the long bones. Affected patients present a CC symmetrically increased thickness of bones, most frequently found CC as an enlarged jawbone, but also an enlargement of the skull, CC ribs, diaphysis of long bones, as well as tubular bones of hands CC and feet. The clinical consequence of increased thickness of the CC skull include facial nerve palsy causing hearing loss, visual CC problems, neurological pain, and, very rarely, blindness as a CC consequence of optic atrophy. Serum alkaline phosphatase levels CC are elevated. {ECO:0000269|PubMed:11836356}. Note=The disease is CC caused by mutations affecting the gene represented in this entry. CC A 52 kb deletion downstream of SOST results in SOST transcription CC suppression causing van Buchem disease. CC -!- DISEASE: Craniodiaphyseal dysplasia autosomal dominant (CDD) CC [MIM:122860]: A severe bone dysplasia characterized by massive CC generalized hyperostosis and sclerosis, especially involving the CC skull and facial bones. The sclerosis is so severe that the CC resulting facial distortion is referred to as 'leontiasis ossea' CC (leonine faces) and the bone deposition results in progressive CC stenosis of craniofacial foramina. Respiratory obstruction due to CC choanal stenosis compromises the clinical outcomes of affected CC patients. {ECO:0000269|PubMed:21221996}. Note=The disease is CC caused by mutations affecting the gene represented in this entry. CC Heterozygous mutations located in the secretion signal of the SOST CC gene prevent sclerostin secretion and can be responsible for CC craniodiaphyseal dysplasia. CC -!- SIMILARITY: Belongs to the sclerostin family. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 CTCK (C-terminal cystine knot-like) domain. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF331844; AAK16158.1; -; mRNA. DR EMBL; AF326736; AAK13451.1; -; Genomic_DNA. DR EMBL; AF326739; AAK13454.1; -; mRNA. DR EMBL; AY358203; AAQ88570.1; -; mRNA. DR EMBL; AY358627; AAQ88990.1; -; mRNA. DR EMBL; AC055813; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC101086; AAI01087.1; -; mRNA. DR EMBL; BC101087; AAI01088.1; -; mRNA. DR EMBL; BC101088; AAI01089.1; -; mRNA. DR EMBL; BC101089; AAI01090.1; -; mRNA. DR CCDS; CCDS11468.1; -. [Q9BQB4-1] DR RefSeq; NP_079513.1; NM_025237.2. [Q9BQB4-1] DR UniGene; Hs.349204; -. DR PDB; 2K8P; NMR; -; A=25-213. DR PDBsum; 2K8P; -. DR ProteinModelPortal; Q9BQB4; -. DR SMR; Q9BQB4; 25-213. DR BioGrid; 119186; 2. DR DIP; DIP-59407N; -. DR IntAct; Q9BQB4; 98. DR STRING; 9606.ENSP00000301691; -. DR DMDM; 20140220; -. DR PaxDb; Q9BQB4; -. DR PRIDE; Q9BQB4; -. DR Ensembl; ENST00000301691; ENSP00000301691; ENSG00000167941. [Q9BQB4-1] DR GeneID; 50964; -. DR KEGG; hsa:50964; -. DR UCSC; uc002iec.1; human. [Q9BQB4-1] DR CTD; 50964; -. DR GeneCards; GC17M041841; -. DR GeneReviews; SOST; -. DR HGNC; HGNC:13771; SOST. DR HPA; CAB025660; -. DR MIM; 122860; phenotype. DR MIM; 239100; phenotype. DR MIM; 269500; phenotype. DR MIM; 605740; gene. DR neXtProt; NX_Q9BQB4; -. DR Orphanet; 1513; Craniodiaphyseal dysplasia. DR Orphanet; 3416; Hyperostosis corticalis generalisata. DR Orphanet; 3152; Sclerosteosis. DR PharmGKB; PA37809; -. DR eggNOG; NOG40285; -. DR GeneTree; ENSGT00390000014900; -. DR HOGENOM; HOG000252934; -. DR HOVERGEN; HBG003729; -. DR InParanoid; Q9BQB4; -. DR KO; K16834; -. DR OMA; DVSEYSC; -. DR OrthoDB; EOG7CVPZN; -. DR PhylomeDB; Q9BQB4; -. DR TreeFam; TF353019; -. DR Reactome; REACT_200643; negative regulation of TCF-dependent signaling by WNT ligand antagonists. DR Reactome; REACT_200777; TCF dependent signaling in response to WNT. DR EvolutionaryTrace; Q9BQB4; -. DR GeneWiki; Sclerostin; -. DR GeneWiki; SOST; -. DR GenomeRNAi; 50964; -. DR NextBio; 53429; -. DR PRO; PR:Q9BQB4; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; Q9BQB4; -. DR CleanEx; HS_SOST; -. DR Genevestigator; Q9BQB4; -. DR GO; GO:0005615; C:extracellular space; IEA:InterPro. DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl. DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0008134; F:transcription factor binding; IDA:UniProtKB. DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IDA:UniProtKB. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:MGI. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL. DR GO; GO:0030279; P:negative regulation of ossification; NAS:UniProtKB. DR GO; GO:0031333; P:negative regulation of protein complex assembly; IDA:BHF-UCL. DR GO; GO:2000054; P:negative regulation of Wnt signaling pathway involved in dorsal/ventral axis specification; IDA:BHF-UCL. DR GO; GO:0001503; P:ossification; IEA:Ensembl. DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:UniProtKB. DR GO; GO:0009612; P:response to mechanical stimulus; IEP:UniProtKB. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR InterPro; IPR008835; Sclerostin/SOSTDC1. DR InterPro; IPR015665; SOST. DR PANTHER; PTHR14903; PTHR14903; 1. DR PANTHER; PTHR14903:SF4; PTHR14903:SF4; 1. DR Pfam; PF05463; Sclerostin; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; KW Direct protein sequencing; Disease mutation; Disulfide bond; KW Extracellular matrix; Glycoprotein; Heparin-binding; KW Reference proteome; Secreted; Signal; Wnt signaling pathway. FT SIGNAL 1 23 {ECO:0000269|PubMed:15340161}. FT CHAIN 24 213 Sclerostin. FT /FTId=PRO_0000033177. FT DOMAIN 82 172 CTCK. FT CARBOHYD 53 53 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 175 175 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 80 134 {ECO:0000269|PubMed:19208630}. FT DISULFID 94 148 {ECO:0000269|PubMed:19208630}. FT DISULFID 105 165 {ECO:0000269|PubMed:19208630}. FT DISULFID 109 167 {ECO:0000269|PubMed:19208630}. FT VAR_SEQ 64 73 RPPHHPFETK -> WPGGRPPSRAPLST (in isoform FT 2). {ECO:0000303|PubMed:12975309}. FT /FTId=VSP_010189. FT VARIANT 21 21 V -> L (in CDD; affects protein FT secretion). FT {ECO:0000269|PubMed:21221996}. FT /FTId=VAR_065766. FT VARIANT 21 21 V -> M (in CDD; de novo mutation; affects FT protein secretion). FT {ECO:0000269|PubMed:21221996}. FT /FTId=VAR_065767. FT VARIANT 167 167 C -> R (in SOST1; leads to retention of FT the mutant protein in the endoplasmic FT reticulum; leads to a complete loss of FT function of the protein). FT {ECO:0000269|PubMed:20583295}. FT /FTId=VAR_063982. FT STRAND 78 80 {ECO:0000244|PDB:2K8P}. FT STRAND 82 87 {ECO:0000244|PDB:2K8P}. FT STRAND 95 98 {ECO:0000244|PDB:2K8P}. FT STRAND 100 105 {ECO:0000244|PDB:2K8P}. FT STRAND 139 147 {ECO:0000244|PDB:2K8P}. FT STRAND 155 162 {ECO:0000244|PDB:2K8P}. SQ SEQUENCE 213 AA; 24031 MW; 30DBD55CE73D5BB2 CRC64; MQLPLALCLV CLLVHTAFRV VEGQGWQAFK NDATEIIPEL GEYPEPPPEL ENNKTMNRAE NGGRPPHHPF ETKDVSEYSC RELHFTRYVT DGPCRSAKPV TELVCSGQCG PARLLPNAIG RGKWWRPSGP DFRCIPDRYR AQRVQLLCPG GEAPRARKVR LVASCKCKRL TRFHNQSELK DFGTEAARPQ KGRKPRPRAR SAKANQAELE NAY //