ID   SMO_HUMAN               Reviewed;         787 AA.
AC   Q99835; A4D1K5;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1997, sequence version 1.
DT   27-MAR-2024, entry version 218.
DE   RecName: Full=Protein smoothened;
DE   AltName: Full=Protein Gx;
DE   Flags: Precursor;
GN   Name=SMO; Synonyms=SMOH;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Embryonic lung;
RX   PubMed=8906787; DOI=10.1038/384129a0;
RA   Stone D.M., Hynes M., Armanini M., Swanson T.A., Gu Q., Johnson R.L.,
RA   Scott M.P., Pennica D., Goddard A., Phillips H., Noll M., Hooper J.E.,
RA   de Sauvage F., Rosenthal A.;
RT   "The tumour-suppressor gene patched encodes a candidate receptor for Sonic
RT   hedgehog.";
RL   Nature 384:129-134(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-535 AND GLN-562.
RX   PubMed=9422511; DOI=10.1038/34201;
RA   Xie J., Murone M., Luoh S.-M., Ryan A., Gu Q., Zhang C., Bonifas J.M.,
RA   Lam C.-W., Hynes M., Goddard A., Rosenthal A., Epstein E.H. Jr.,
RA   de Sauvage F.J.;
RT   "Activating Smoothened mutations in sporadic basal-cell carcinoma.";
RL   Nature 391:90-92(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Jiang N., Zeng Z.Y., Li G.Y.;
RT   "Cloning and identification of Gx gene in NPC.";
RL   Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12690205; DOI=10.1126/science.1083423;
RA   Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA   Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA   Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA   Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA   Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA   Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA   Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA   Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA   Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA   Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA   Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA   Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA   Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA   Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA   Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA   Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA   Adams M.D., Tsui L.-C.;
RT   "Human chromosome 7: DNA sequence and biology.";
RL   Science 300:767-772(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   FUNCTION, AND INTERACTION WITH KIF7.
RX   PubMed=19592253; DOI=10.1016/j.cub.2009.06.046;
RA   Endoh-Yamagami S., Evangelista M., Wilson D., Wen X., Theunissen J.W.,
RA   Phamluong K., Davis M., Scales S.J., Solloway M.J., de Sauvage F.J.,
RA   Peterson A.S.;
RT   "The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh
RT   signal transduction during development.";
RL   Curr. Biol. 19:1320-1326(2009).
RN   [8]
RP   INTERACTION WITH GAS8.
RX   PubMed=21659505; DOI=10.1074/jbc.m111.234666;
RA   Evron T., Philipp M., Lu J., Meloni A.R., Burkhalter M., Chen W.,
RA   Caron M.G.;
RT   "Growth arrest specific 8 (Gas8) and G protein-coupled receptor kinase 2
RT   (GRK2) cooperate in the control of Smoothened signaling.";
RL   J. Biol. Chem. 286:27676-27686(2011).
RN   [9]
RP   ASSOCIATION WITH THE BBSOME COMPLEX, INTERACTION WITH BBS5 AND BBS7, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=22072986; DOI=10.1371/journal.pgen.1002358;
RA   Seo S., Zhang Q., Bugge K., Breslow D.K., Searby C.C., Nachury M.V.,
RA   Sheffield V.C.;
RT   "A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and
RT   Smoothened.";
RL   PLoS Genet. 7:E1002358-E1002358(2011).
RN   [10]
RP   INVOLVEMENT IN CRJS, AND VARIANT CRJS PHE-412.
RX   PubMed=27236920; DOI=10.1016/j.ajhg.2016.04.007;
RA   Twigg S.R., Hufnagel R.B., Miller K.A., Zhou Y., McGowan S.J., Taylor J.,
RA   Craft J., Taylor J.C., Santoro S.L., Huang T., Hopkin R.J., Brady A.F.,
RA   Clayton-Smith J., Clericuzio C.L., Grange D.K., Groesser L., Hafner C.,
RA   Horn D., Temple I.K., Dobyns W.B., Curry C.J., Jones M.C., Wilkie A.O.;
RT   "A recurrent mosaic mutation in SMO, encoding the hedgehog signal
RT   transducer smoothened, is the major cause of Curry-Jones syndrome.";
RL   Am. J. Hum. Genet. 98:1256-1265(2016).
RN   [11] {ECO:0007744|PDB:4JKV}
RP   X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 190-555 IN COMPLEX WITH
RP   ANTAGONIST, SUBUNIT, AND DISULFIDE BONDS.
RX   PubMed=23636324; DOI=10.1038/nature12167;
RA   Wang C., Wu H., Katritch V., Han G.W., Huang X.P., Liu W., Siu F.Y.,
RA   Roth B.L., Cherezov V., Stevens R.C.;
RT   "Structure of the human smoothened receptor bound to an antitumour agent.";
RL   Nature 497:338-343(2013).
RN   [12] {ECO:0007744|PDB:7ZI0}
RP   X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 32-555 OF MUTANT PHE-329 IN
RP   COMPLEX WITH CHOLESTEROL, DOMAIN, AND DISULFIDE BONDS.
RX   PubMed=35658032; DOI=10.1126/sciadv.abm5563;
RA   Kinnebrew M., Woolley R.E., Ansell T.B., Byrne E.F.X., Frigui S.,
RA   Luchetti G., Sircar R., Nachtergaele S., Mydock-McGrane L., Krishnan K.,
RA   Newstead S., Sansom M.S.P., Covey D.F., Siebold C., Rohatgi R.;
RT   "Patched 1 regulates Smoothened by controlling sterol binding to its
RT   extracellular cysteine-rich domain.";
RL   Sci. Adv. 8:eabm5563-eabm5563(2022).
RN   [13]
RP   VARIANT CRJS PHE-412, VARIANT LEU-535, CHARACTERIZATION OF VARIANT CRJS
RP   PHE-412, AND CHARACTERIZATION OF VARIANT LEU-535.
RX   PubMed=24859340; DOI=10.1038/ng.2986;
RA   Sweeney R.T., McClary A.C., Myers B.R., Biscocho J., Neahring L.,
RA   Kwei K.A., Qu K., Gong X., Ng T., Jones C.D., Varma S., Odegaard J.I.,
RA   Sugiyama T., Koyota S., Rubin B.P., Troxell M.L., Pelham R.J.,
RA   Zehnder J.L., Beachy P.A., Pollack J.R., West R.B.;
RT   "Identification of recurrent SMO and BRAF mutations in ameloblastomas.";
RL   Nat. Genet. 46:722-725(2014).
CC   -!- FUNCTION: G protein-coupled receptor which associates with the patched
CC       protein (PTCH) to transduce hedgehog protein signaling. Binding of
CC       sonic hedgehog (SHH) to its receptor patched prevents inhibition of
CC       smoothened (SMO) by patched. When active, SMO binds to and sequesters
CC       protein kinase A catalytic subunit PRKACA at the cell membrane,
CC       preventing PRKACA-mediated phosphorylation of GLI transcription factors
CC       which releases the GLI proteins from PRKACA-mediated inhibition and
CC       allows for transcriptional activation of hedgehog pathway target genes
CC       (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3
CC       in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base
CC       to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2
CC       activation (By similarity). {ECO:0000250|UniProtKB:P56726,
CC       ECO:0000269|PubMed:19592253}.
CC   -!- SUBUNIT: Homodimer (PubMed:23636324). Interacts (via C-terminus) with
CC       protein kinase A catalytic subunit PRKACA; interacts with free PRKACA
CC       subunits and the interaction leads to sequestration of PRKACA at the
CC       membrane, preventing PRKACA-mediated phosphorylation of GLI
CC       transcription factors (By similarity). Interacts with ARRB2 (By
CC       similarity). Interacts with KIF7 (PubMed:19592253). Interacts with BBS5
CC       and BBS7; the interactions are indicative for the association of SMO
CC       with the BBsome complex to facilitate ciliary localization of SMO
CC       (PubMed:22072986). Interacts with DLG5 and SDCBP (By similarity).
CC       Interacts with GAS8/DRC4 (PubMed:21659505).
CC       {ECO:0000250|UniProtKB:P56726, ECO:0000269|PubMed:19592253,
CC       ECO:0000269|PubMed:21659505, ECO:0000269|PubMed:22072986,
CC       ECO:0000269|PubMed:23636324}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P56726};
CC       Multi-pass membrane protein {ECO:0000255}. Cell projection, cilium
CC       {ECO:0000269|PubMed:22072986}. Note=Cilium localization is promoted by
CC       SHH and is required for activity. {ECO:0000250|UniProtKB:P56726}.
CC   -!- DOMAIN: The N-terminal extracellular domain mediates sterol-binding
CC       which is required for maximal activation of signaling
CC       (PubMed:24859340). Contains a second sterol-binding site within the
CC       seven-transmembrane pocket which is also required for activation (By
CC       similarity). The activating sterol is likely to be cholesterol
CC       (PubMed:35658032). The extracellular site is required for SHH-induced
CC       activity while the site within the transmembrane pocket regulates basal
CC       signaling in the absence of SHH (PubMed:35658032).
CC       {ECO:0000250|UniProtKB:P56726, ECO:0000269|PubMed:24859340,
CC       ECO:0000269|PubMed:35658032}.
CC   -!- PTM: Phosphorylation by GRK kinases is required for interaction with
CC       protein kinase A catalytic subunit PRKACA.
CC       {ECO:0000250|UniProtKB:P56726}.
CC   -!- DISEASE: Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem
CC       disorder characterized by patchy skin lesions, polysyndactyly, diverse
CC       cerebral malformations, unicoronal craniosynostosis, iris colobomas,
CC       microphthalmia, and intestinal malrotation with myofibromas or
CC       hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry. 8 individuals have been identified with the disease-
CC       causing mutation Phe-412 and all were mosaic. The mutation could not be
CC       reliably detected in blood, greatest success rates were obtained with
CC       affected tissues obtained by invasive procedures. It is thought that
CC       the mutation has arisen postzygotically early during embryonic
CC       development (PubMed:27236920). This mutation has also been identified
CC       in ameloblastoma, medulloblastoma, meningioma, and basal cell
CC       carcinoma, and has been reported as the oncogenic driver in some of
CC       these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340,
CC       ECO:0000269|PubMed:27236920}.
CC   -!- SIMILARITY: Belongs to the G-protein coupled receptor Fz/Smo family.
CC       {ECO:0000305}.
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DR   EMBL; U84401; AAB41788.1; -; mRNA.
DR   EMBL; AF114821; AAD17202.1; -; Genomic_DNA.
DR   EMBL; AF114819; AAD17202.1; JOINED; Genomic_DNA.
DR   EMBL; AF114820; AAD17202.1; JOINED; Genomic_DNA.
DR   EMBL; AF120103; AAF31757.1; -; mRNA.
DR   EMBL; AF071494; AAC24863.1; -; mRNA.
DR   EMBL; CH236950; EAL24102.1; -; Genomic_DNA.
DR   EMBL; CH471070; EAW83715.1; -; Genomic_DNA.
DR   EMBL; BC009989; AAH09989.1; -; mRNA.
DR   CCDS; CCDS5811.1; -.
DR   RefSeq; NP_005622.1; NM_005631.4.
DR   PDB; 4JKV; X-ray; 2.45 A; A/B=190-555.
DR   PDB; 4N4W; X-ray; 2.80 A; A=190-555.
DR   PDB; 4O9R; X-ray; 3.20 A; A=190-433, A=441-555.
DR   PDB; 4QIM; X-ray; 2.61 A; A=190-433, A=441-555.
DR   PDB; 4QIN; X-ray; 2.60 A; A=190-433, A=441-555.
DR   PDB; 5L7D; X-ray; 3.20 A; A/B=32-428, A/B=443-555.
DR   PDB; 5L7I; X-ray; 3.30 A; A/B=32-428, A/B=443-555.
DR   PDB; 5V56; X-ray; 2.90 A; A/B=53-437, A/B=444-558.
DR   PDB; 5V57; X-ray; 3.00 A; A/B=58-437, A/B=444-558.
DR   PDB; 6OT0; EM; 3.90 A; R=1-555.
DR   PDB; 6XBJ; EM; 3.88 A; R=1-644.
DR   PDB; 6XBK; EM; 3.24 A; R=1-644.
DR   PDB; 6XBL; EM; 3.90 A; R=1-644.
DR   PDB; 6XBM; EM; 3.15 A; R=1-644.
DR   PDB; 7ZI0; X-ray; 3.00 A; A/B=32-428, A/B=443-555.
DR   PDBsum; 4JKV; -.
DR   PDBsum; 4N4W; -.
DR   PDBsum; 4O9R; -.
DR   PDBsum; 4QIM; -.
DR   PDBsum; 4QIN; -.
DR   PDBsum; 5L7D; -.
DR   PDBsum; 5L7I; -.
DR   PDBsum; 5V56; -.
DR   PDBsum; 5V57; -.
DR   PDBsum; 6OT0; -.
DR   PDBsum; 6XBJ; -.
DR   PDBsum; 6XBK; -.
DR   PDBsum; 6XBL; -.
DR   PDBsum; 6XBM; -.
DR   PDBsum; 7ZI0; -.
DR   AlphaFoldDB; Q99835; -.
DR   EMDB; EMD-20190; -.
DR   EMDB; EMD-22117; -.
DR   EMDB; EMD-22118; -.
DR   EMDB; EMD-22119; -.
DR   EMDB; EMD-22120; -.
DR   SMR; Q99835; -.
DR   BioGRID; 112492; 53.
DR   DIP; DIP-34574N; -.
DR   IntAct; Q99835; 35.
DR   MINT; Q99835; -.
DR   STRING; 9606.ENSP00000249373; -.
DR   BindingDB; Q99835; -.
DR   ChEMBL; CHEMBL5971; -.
DR   DrugBank; DB01047; Fluocinonide.
DR   DrugBank; DB11978; Glasdegib.
DR   DrugBank; DB06786; Halcinonide.
DR   DrugBank; DB09143; Sonidegib.
DR   DrugBank; DB08828; Vismodegib.
DR   DrugCentral; Q99835; -.
DR   GuidetoPHARMACOLOGY; 239; -.
DR   TCDB; 9.A.14.16.4; the g-protein-coupled receptor (gpcr) family.
DR   GlyConnect; 2079; 1 N-Linked glycan (1 site).
DR   GlyCosmos; Q99835; 5 sites, 4 glycans.
DR   GlyGen; Q99835; 6 sites, 2 N-linked glycans (1 site), 3 O-linked glycans (3 sites).
DR   iPTMnet; Q99835; -.
DR   PhosphoSitePlus; Q99835; -.
DR   BioMuta; SMO; -.
DR   DMDM; 6226142; -.
DR   EPD; Q99835; -.
DR   jPOST; Q99835; -.
DR   MassIVE; Q99835; -.
DR   PaxDb; 9606-ENSP00000249373; -.
DR   PeptideAtlas; Q99835; -.
DR   ProteomicsDB; 78499; -.
DR   Antibodypedia; 31982; 639 antibodies from 38 providers.
DR   DNASU; 6608; -.
DR   Ensembl; ENST00000249373.8; ENSP00000249373.3; ENSG00000128602.11.
DR   GeneID; 6608; -.
DR   KEGG; hsa:6608; -.
DR   MANE-Select; ENST00000249373.8; ENSP00000249373.3; NM_005631.5; NP_005622.1.
DR   UCSC; uc003vor.4; human.
DR   AGR; HGNC:11119; -.
DR   CTD; 6608; -.
DR   DisGeNET; 6608; -.
DR   GeneCards; SMO; -.
DR   GeneReviews; SMO; -.
DR   HGNC; HGNC:11119; SMO.
DR   HPA; ENSG00000128602; Low tissue specificity.
DR   MalaCards; SMO; -.
DR   MIM; 601500; gene.
DR   MIM; 601707; phenotype.
DR   neXtProt; NX_Q99835; -.
DR   OpenTargets; ENSG00000128602; -.
DR   Orphanet; 1553; Curry-Jones syndrome.
DR   Orphanet; 388; Hirschsprung disease.
DR   Orphanet; 2495; Meningioma.
DR   PharmGKB; PA35968; -.
DR   VEuPathDB; HostDB:ENSG00000128602; -.
DR   eggNOG; KOG3577; Eukaryota.
DR   GeneTree; ENSGT00940000157206; -.
DR   HOGENOM; CLU_007873_3_1_1; -.
DR   InParanoid; Q99835; -.
DR   OMA; FLKCTPD; -.
DR   OrthoDB; 2902735at2759; -.
DR   PhylomeDB; Q99835; -.
DR   TreeFam; TF106460; -.
DR   PathwayCommons; Q99835; -.
DR   Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR   Reactome; R-HSA-5610787; Hedgehog 'off' state.
DR   Reactome; R-HSA-5620922; BBSome-mediated cargo-targeting to cilium.
DR   Reactome; R-HSA-5632684; Hedgehog 'on' state.
DR   Reactome; R-HSA-5635838; Activation of SMO.
DR   SignaLink; Q99835; -.
DR   SIGNOR; Q99835; -.
DR   BioGRID-ORCS; 6608; 15 hits in 1154 CRISPR screens.
DR   ChiTaRS; SMO; human.
DR   GeneWiki; Smoothened; -.
DR   GenomeRNAi; 6608; -.
DR   Pharos; Q99835; Tclin.
DR   PRO; PR:Q99835; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q99835; Protein.
DR   Bgee; ENSG00000128602; Expressed in ventricular zone and 143 other cell types or tissues.
DR   ExpressionAtlas; Q99835; baseline and differential.
DR   GO; GO:0097731; C:9+0 non-motile cilium; IEA:Ensembl.
DR   GO; GO:0005814; C:centriole; IEA:Ensembl.
DR   GO; GO:0060170; C:ciliary membrane; TAS:Reactome.
DR   GO; GO:0097542; C:ciliary tip; TAS:Reactome.
DR   GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR   GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR   GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
DR   GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:Ensembl.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:BHF-UCL.
DR   GO; GO:0005770; C:late endosome; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0004862; F:cAMP-dependent protein kinase inhibitor activity; IDA:FlyBase.
DR   GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW.
DR   GO; GO:0008142; F:oxysterol binding; ISS:UniProtKB.
DR   GO; GO:0005113; F:patched binding; IPI:BHF-UCL.
DR   GO; GO:0034236; F:protein kinase A catalytic subunit binding; ISS:UniProtKB.
DR   GO; GO:0140311; F:protein sequestering activity; ISS:UniProtKB.
DR   GO; GO:0009952; P:anterior/posterior pattern specification; IEA:Ensembl.
DR   GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR   GO; GO:0048143; P:astrocyte activation; IEA:Ensembl.
DR   GO; GO:0060413; P:atrial septum morphogenesis; IEA:Ensembl.
DR   GO; GO:0001708; P:cell fate specification; IEA:Ensembl.
DR   GO; GO:0071397; P:cellular response to cholesterol; ISS:BHF-UCL.
DR   GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR   GO; GO:0021953; P:central nervous system neuron differentiation; IEA:Ensembl.
DR   GO; GO:0021696; P:cerebellar cortex morphogenesis; IEA:Ensembl.
DR   GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR   GO; GO:0071679; P:commissural neuron axon guidance; IBA:GO_Central.
DR   GO; GO:0060242; P:contact inhibition; IMP:BHF-UCL.
DR   GO; GO:0021542; P:dentate gyrus development; IEA:Ensembl.
DR   GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; ISS:BHF-UCL.
DR   GO; GO:0071542; P:dopaminergic neuron differentiation; IEA:Ensembl.
DR   GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR   GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR   GO; GO:0060684; P:epithelial-mesenchymal cell signaling; IEA:Ensembl.
DR   GO; GO:0048853; P:forebrain morphogenesis; ISS:BHF-UCL.
DR   GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR   GO; GO:0031069; P:hair follicle morphogenesis; IEA:Ensembl.
DR   GO; GO:0001947; P:heart looping; ISS:BHF-UCL.
DR   GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR   GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR   GO; GO:0070986; P:left/right axis specification; IEA:Ensembl.
DR   GO; GO:0060644; P:mammary gland epithelial cell differentiation; IEA:Ensembl.
DR   GO; GO:0072285; P:mesenchymal to epithelial transition involved in metanephric renal vesicle formation; ISS:UniProtKB.
DR   GO; GO:0007494; P:midgut development; ISS:BHF-UCL.
DR   GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR   GO; GO:0051451; P:myoblast migration; IEA:Ensembl.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0043392; P:negative regulation of DNA binding; ISS:UniProtKB.
DR   GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IEA:Ensembl.
DR   GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB.
DR   GO; GO:0051799; P:negative regulation of hair follicle development; IEA:Ensembl.
DR   GO; GO:0001933; P:negative regulation of protein phosphorylation; ISS:UniProtKB.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0001755; P:neural crest cell migration; IEA:Ensembl.
DR   GO; GO:0007405; P:neuroblast proliferation; IEA:Ensembl.
DR   GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR   GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR   GO; GO:0061113; P:pancreas morphogenesis; IEA:Ensembl.
DR   GO; GO:0007389; P:pattern specification process; IBA:GO_Central.
DR   GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; ISS:UniProtKB.
DR   GO; GO:0030335; P:positive regulation of cell migration; IMP:ARUK-UCL.
DR   GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IEA:Ensembl.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:0007228; P:positive regulation of hh target transcription factor activity; ISS:BHF-UCL.
DR   GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IEA:Ensembl.
DR   GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR   GO; GO:0002052; P:positive regulation of neuroblast proliferation; IEA:Ensembl.
DR   GO; GO:0046622; P:positive regulation of organ growth; IEA:Ensembl.
DR   GO; GO:0042307; P:positive regulation of protein import into nucleus; IEA:Ensembl.
DR   GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl.
DR   GO; GO:0050821; P:protein stabilization; IEA:Ensembl.
DR   GO; GO:2000826; P:regulation of heart morphogenesis; ISS:BHF-UCL.
DR   GO; GO:1904672; P:regulation of somatic stem cell population maintenance; IEA:Ensembl.
DR   GO; GO:0048741; P:skeletal muscle fiber development; IEA:Ensembl.
DR   GO; GO:0048745; P:smooth muscle tissue development; IEP:UniProtKB.
DR   GO; GO:0007224; P:smoothened signaling pathway; IDA:FlyBase.
DR   GO; GO:0061053; P:somite development; ISS:BHF-UCL.
DR   GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IEA:Ensembl.
DR   GO; GO:0021794; P:thalamus development; IEA:Ensembl.
DR   GO; GO:0003323; P:type B pancreatic cell development; IEA:Ensembl.
DR   GO; GO:0001570; P:vasculogenesis; IEA:Ensembl.
DR   GO; GO:0007371; P:ventral midline determination; ISS:BHF-UCL.
DR   CDD; cd15030; 7tmF_SMO_homolog; 1.
DR   CDD; cd07451; CRD_SMO; 1.
DR   Gene3D; 1.10.2000.10; Frizzled cysteine-rich domain; 1.
DR   Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1.
DR   InterPro; IPR015526; Frizzled/SFRP.
DR   InterPro; IPR000539; Frizzled/Smoothened_7TM.
DR   InterPro; IPR020067; Frizzled_dom.
DR   InterPro; IPR036790; Frizzled_dom_sf.
DR   InterPro; IPR017981; GPCR_2-like_7TM.
DR   InterPro; IPR035683; SMO_7TM.
DR   InterPro; IPR041771; SMO_CRD.
DR   PANTHER; PTHR11309; FRIZZLED; 1.
DR   PANTHER; PTHR11309:SF35; SMOOTHENED HOMOLOG; 1.
DR   Pfam; PF01534; Frizzled; 1.
DR   Pfam; PF01392; Fz; 1.
DR   PRINTS; PR00489; FRIZZLED.
DR   SMART; SM00063; FRI; 1.
DR   SMART; SM01330; Frizzled; 1.
DR   SUPFAM; SSF63501; Frizzled cysteine-rich domain; 1.
DR   PROSITE; PS50038; FZ; 1.
DR   PROSITE; PS50261; G_PROTEIN_RECEP_F2_4; 1.
DR   Genevisible; Q99835; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Cell membrane; Cell projection; Developmental protein;
KW   Disease variant; Disulfide bond; G-protein coupled receptor; Glycoprotein;
KW   Membrane; Phosphoprotein; Receptor; Reference proteome; Signal; Transducer;
KW   Transmembrane; Transmembrane helix.
FT   SIGNAL          1..27
FT                   /evidence="ECO:0000255"
FT   CHAIN           28..787
FT                   /note="Protein smoothened"
FT                   /id="PRO_0000013015"
FT   TOPO_DOM        28..233
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        234..254
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        255..262
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        263..283
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        284..314
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        315..335
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        336..358
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        359..379
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        380..402
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        403..423
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        424..451
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        452..472
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        473..524
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        525..545
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        546..787
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          65..181
FT                   /note="FZ"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT   REGION          30..60
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          538..569
FT                   /note="Interaction with BBS5 and BBS7"
FT                   /evidence="ECO:0000269|PubMed:22072986"
FT   REGION          570..653
FT                   /note="Required for interaction with PRKACA"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   REGION          581..593
FT                   /note="Interaction with DLG5"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   REGION          667..704
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        686..703
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         95
FT                   /ligand="cholesterol"
FT                   /ligand_id="ChEBI:CHEBI:16113"
FT                   /evidence="ECO:0000269|PubMed:35658032,
FT                   ECO:0007744|PDB:7ZI0"
FT   BINDING         394
FT                   /ligand="cholesterol"
FT                   /ligand_id="ChEBI:CHEBI:16113"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         556
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         574
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         590
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         593
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         595
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         638
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         640
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         644
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   MOD_RES         662
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P56726"
FT   CARBOHYD        35
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        188
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        309
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        64..178
FT                   /evidence="ECO:0000269|PubMed:35658032,
FT                   ECO:0007744|PDB:7ZI0"
FT   DISULFID        70..134
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:7ZI0"
FT   DISULFID        78..127
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:7ZI0"
FT   DISULFID        118..154
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:7ZI0"
FT   DISULFID        147..169
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:7ZI0"
FT   DISULFID        193..213
FT                   /evidence="ECO:0000269|PubMed:23636324,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:4JKV,
FT                   ECO:0007744|PDB:7ZI0"
FT   DISULFID        217..295
FT                   /evidence="ECO:0000269|PubMed:23636324,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:4JKV,
FT                   ECO:0007744|PDB:7ZI0"
FT   DISULFID        314..390
FT                   /evidence="ECO:0000269|PubMed:23636324,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:4JKV,
FT                   ECO:0007744|PDB:7ZI0"
FT   DISULFID        490..507
FT                   /evidence="ECO:0000269|PubMed:23636324,
FT                   ECO:0000269|PubMed:35658032, ECO:0007744|PDB:4JKV,
FT                   ECO:0007744|PDB:7ZI0"
FT   VARIANT         412
FT                   /note="L -> F (in CRJS; constitutive activation of the
FT                   smoothened signaling pathway; dbSNP:rs879255280)"
FT                   /evidence="ECO:0000269|PubMed:24859340,
FT                   ECO:0000269|PubMed:27236920"
FT                   /id="VAR_077087"
FT   VARIANT         473
FT                   /note="D -> H (in dbSNP:rs17710891)"
FT                   /id="VAR_037891"
FT   VARIANT         535
FT                   /note="W -> L (in basal cell carcinoma and ameloblastoma
FT                   samples; somatic mutation; constitutive activation of the
FT                   smoothened signaling pathway; dbSNP:rs121918347)"
FT                   /evidence="ECO:0000269|PubMed:24859340,
FT                   ECO:0000269|PubMed:9422511"
FT                   /id="VAR_007848"
FT   VARIANT         562
FT                   /note="R -> Q (in basal cell carcinoma samples; somatic
FT                   mutation; dbSNP:rs121918348)"
FT                   /evidence="ECO:0000269|PubMed:9422511"
FT                   /id="VAR_007849"
FT   HELIX           62..64
FT                   /evidence="ECO:0007829|PDB:7ZI0"
FT   STRAND          65..67
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          76..78
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          86..88
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          90..92
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           99..109
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           110..113
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           116..130
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          136..140
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           144..151
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   TURN            152..154
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           155..160
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   TURN            165..167
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   TURN            171..173
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          176..178
FT                   /evidence="ECO:0007829|PDB:6XBK"
FT   TURN            182..184
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   STRAND          190..192
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          197..199
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           203..205
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          210..218
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           224..254
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           256..259
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   TURN            262..265
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           266..282
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           283..285
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           289..294
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          299..301
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          304..306
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          308..310
FT                   /evidence="ECO:0007829|PDB:7ZI0"
FT   HELIX           313..347
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   TURN            354..356
FT                   /evidence="ECO:0007829|PDB:4QIM"
FT   HELIX           361..378
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          381..384
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   TURN            385..388
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          389..395
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           397..403
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           405..432
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          436..442
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           443..492
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          496..498
FT                   /evidence="ECO:0007829|PDB:7ZI0"
FT   STRAND          501..503
FT                   /evidence="ECO:0007829|PDB:5V56"
FT   HELIX           515..532
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           533..536
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   HELIX           539..548
FT                   /evidence="ECO:0007829|PDB:4JKV"
FT   STRAND          554..558
FT                   /evidence="ECO:0007829|PDB:5V57"
SQ   SEQUENCE   787 AA;  86397 MW;  8B4C459B34D13F83 CRC64;
     MAAARPARGP ELPLLGLLLL LLLGDPGRGA ASSGNATGPG PRSAGGSARR SAAVTGPPPP
     LSHCGRAAPC EPLRYNVCLG SVLPYGATST LLAGDSDSQE EAHGKLVLWS GLRNAPRCWA
     VIQPLLCAVY MPKCENDRVE LPSRTLCQAT RGPCAIVERE RGWPDFLRCT PDRFPEGCTN
     EVQNIKFNSS GQCEVPLVRT DNPKSWYEDV EGCGIQCQNP LFTEAEHQDM HSYIAAFGAV
     TGLCTLFTLA TFVADWRNSN RYPAVILFYV NACFFVGSIG WLAQFMDGAR REIVCRADGT
     MRLGEPTSNE TLSCVIIFVI VYYALMAGVV WFVVLTYAWH TSFKALGTTY QPLSGKTSYF
     HLLTWSLPFV LTVAILAVAQ VDGDSVSGIC FVGYKNYRYR AGFVLAPIGL VLIVGGYFLI
     RGVMTLFSIK SNHPGLLSEK AASKINETML RLGIFGFLAF GFVLITFSCH FYDFFNQAEW
     ERSFRDYVLC QANVTIGLPT KQPIPDCEIK NRPSLLVEKI NLFAMFGTGI AMSTWVWTKA
     TLLIWRRTWC RLTGQSDDEP KRIKKSKMIA KAFSKRHELL QNPGQELSFS MHTVSHDGPV
     AGLAFDLNEP SADVSSAWAQ HVTKMVARRG AILPQDISVT PVATPVPPEE QANLWLVEAE
     ISPELQKRLG RKKKRRKRKK EVCPLAPPPE LHPPAPAPST IPRLPQLPRQ KCLVAAGAWG
     AGDSCRQGAW TLVSNPFCPE PSPPQDPFLP SAPAPVAWAH GRRQGLGPIH SRTNLMDTEL
     MDADSDF
//