ID SMO_MOUSE Reviewed; 793 AA. AC P56726; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 24-JAN-2024, entry version 178. DE RecName: Full=Protein smoothened; DE Flags: Precursor; GN Name=Smo; Synonyms=Smoh; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9196051; DOI=10.1006/bbrc.1997.6750; RA Akiyama H., Shigeno C., Hiraki Y., Shukunami C., Kohno H., Akagi M., RA Konishi J., Nakamura T.; RT "Cloning of a mouse Smoothened cDNA and expression patterns of hedgehog RT signalling molecules during chondrogenesis and cartilage differentiation in RT clonal mouse EC cells, ATDC5."; RL Biochem. Biophys. Res. Commun. 235:142-147(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [3] RP INTERACTION WITH ARRB2. RX PubMed=15618519; DOI=10.1126/science.1104135; RA Chen W., Ren X.R., Nelson C.D., Barak L.S., Chen J.K., Beachy P.A., RA de Sauvage F., Lefkowitz R.J.; RT "Activity-dependent internalization of smoothened mediated by beta-arrestin RT 2 and GRK2."; RL Science 306:2257-2260(2004). RN [4] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF RP 549-TRP-ARG-550. RX PubMed=16136078; DOI=10.1038/nature04117; RA Corbit K.C., Aanstad P., Singla V., Norman A.R., Stainier D.Y., RA Reiter J.F.; RT "Vertebrate Smoothened functions at the primary cilium."; RL Nature 437:1018-1021(2005). RN [5] RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF CYS-151. RX PubMed=19464178; DOI=10.1016/j.cub.2009.04.053; RA Aanstad P., Santos N., Corbit K.C., Scherz P.J., Trinh L.A., RA Salvenmoser W., Huisken J., Reiter J.F., Stainier D.Y.; RT "The extracellular domain of Smoothened regulates ciliary localization and RT is required for high-level Hh signaling."; RL Curr. Biol. 19:1034-1039(2009). RN [6] RP SUBCELLULAR LOCATION, AND 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 [7] RP ASSOCIATION WITH THE BBSOME COMPLEX, AND INTERACTION WITH BBS5 AND BBS7. 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 [8] RP DOMAIN, AND MUTAGENESIS OF PRO-88; LEU-112; GLY-115; LEU-116; ASN-118; RP PRO-120; PRO-128; TYR-134; LEU-150; GLU-162; ARG-165; GLY-166; PRO-168 AND RP PHE-170. RX PubMed=24171105; DOI=10.7554/elife.01340; RA Nachtergaele S., Whalen D.M., Mydock L.K., Zhao Z., Malinauskas T., RA Krishnan K., Ingham P.W., Covey D.F., Siebold C., Rohatgi R.; RT "Structure and function of the Smoothened extracellular domain in RT vertebrate Hedgehog signaling."; RL Elife 2:e01340-e01340(2013). RN [9] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 112-LEU--ALA-119; LEU-112; TRP-113 RP AND SER-114. RX PubMed=23831757; DOI=10.1038/nchembio.1290; RA Nedelcu D., Liu J., Xu Y., Jao C., Salic A.; RT "Oxysterol binding to the extracellular domain of Smoothened in Hedgehog RT signaling."; RL Nat. Chem. Biol. 9:557-564(2013). RN [10] RP FUNCTION, INTERACTION WITH DLG5; KIF7 AND SDCBP, AND SUBCELLULAR LOCATION. RX PubMed=25644602; DOI=10.1101/gad.252676.114; RA Chong Y.C., Mann R.K., Zhao C., Kato M., Beachy P.A.; RT "Bifurcating action of Smoothened in Hedgehog signaling is mediated by RT Dlg5."; RL Genes Dev. 29:262-276(2015). RN [11] RP FUNCTION, INTERACTION WITH PRKACA, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT SER-560; SER-578; SER-594; THR-597; SER-599; SER-642; RP THR-644; THR-648 AND SER-666. RX PubMed=33886552; DOI=10.1371/journal.pbio.3001191; RA Arveseth C.D., Happ J.T., Hedeen D.S., Zhu J.F., Capener J.L., RA Klatt Shaw D., Deshpande I., Liang J., Xu J., Stubben S.L., Nelson I.B., RA Walker M.F., Kawakami K., Inoue A., Krogan N.J., Grunwald D.J., RA Huettenhain R., Manglik A., Myers B.R.; RT "Smoothened transduces Hedgehog signals via activity-dependent RT sequestration of PKA catalytic subunits."; RL PLoS Biol. 19:e3001191-e3001191(2021). RN [12] RP DOMAIN, AND MUTAGENESIS OF ASP-99; VAL-333 AND TYR-398. 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] {ECO:0007744|PDB:6O3C} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 64-566 IN COMPLEX WITH RP CHOLESTEROL, DOMAIN, DISULFIDE BONDS, AND MUTAGENESIS OF VAL-333; VAL-408; RP ILE-412; GLY-420; ALA-463 AND THR-470. RX PubMed=31263273; DOI=10.1038/s41586-019-1355-4; RA Deshpande I., Liang J., Hedeen D., Roberts K.J., Zhang Y., Ha B., RA Latorraca N.R., Faust B., Dror R.O., Beachy P.A., Myers B.R., Manglik A.; RT "Smoothened stimulation by membrane sterols drives Hedgehog pathway RT activity."; RL Nature 571:284-288(2019). 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 (By similarity). When active, SMO binds to CC and sequesters protein kinase A catalytic subunit PRKACA at the cell CC membrane, preventing PRKACA-mediated phosphorylation of GLI CC transcription factors which releases the GLI proteins from PRKACA- CC mediated inhibition and allows for transcriptional activation of CC hedgehog pathway target genes (PubMed:33886552). Required for the CC accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 CC at the ciliary base to induce the accumulation of KIF7 and GLI2 at the CC ciliary tip for GLI2 activation (PubMed:25644602). CC {ECO:0000250|UniProtKB:Q99835, ECO:0000269|PubMed:25644602, CC ECO:0000269|PubMed:33886552}. CC -!- SUBUNIT: Homodimer (By similarity). 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 (PubMed:33886552). Interacts with ARRB2 CC (PubMed:15618519). Interacts with BBS5 and BBS7; the interactions are CC indicative for the association of SMO with the BBsome complex to CC facilitate ciliary localization of SMO (PubMed:22072986). Interacts CC with KIF7, DLG5 and SDCBP (PubMed:25644602). Interacts with GAS8/DRC4 CC (PubMed:21659505). {ECO:0000250|UniProtKB:Q99835, CC ECO:0000269|PubMed:15618519, ECO:0000269|PubMed:21659505, CC ECO:0000269|PubMed:22072986, ECO:0000269|PubMed:25644602, CC ECO:0000269|PubMed:33886552}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16136078, CC ECO:0000269|PubMed:33886552}; Multi-pass membrane protein CC {ECO:0000255}. Cell projection, cilium {ECO:0000269|PubMed:16136078, CC ECO:0000269|PubMed:19464178, ECO:0000269|PubMed:21659505, CC ECO:0000269|PubMed:23831757, ECO:0000269|PubMed:25644602}. Note=Cilium CC localization is promoted by SHH and is required for activity. CC {ECO:0000269|PubMed:16136078, ECO:0000269|PubMed:19464178}. CC -!- TISSUE SPECIFICITY: During early somite stages of embryonic CC development, modestly up-regulated in the cells of the node (at protein CC level). {ECO:0000269|PubMed:16136078}. CC -!- DOMAIN: The N-terminal extracellular domain mediates sterol-binding CC which is required for maximal activation of signaling (PubMed:24171105, CC PubMed:19464178). Contains a second sterol-binding site within the CC seven-transmembrane pocket which is also required for activation CC (PubMed:31263273). The activating sterol is likely to be cholesterol CC (PubMed:31263273, PubMed:35658032). The extracellular site is required CC for SHH-induced activity while the site within the transmembrane pocket CC regulates basal signaling in the absence of SHH (PubMed:35658032). CC {ECO:0000269|PubMed:19464178, ECO:0000269|PubMed:24171105, CC ECO:0000269|PubMed:31263273, ECO:0000269|PubMed:35658032}. CC -!- PTM: Phosphorylation by GRK kinases is required for interaction with CC protein kinase A catalytic subunit PRKACA. CC {ECO:0000269|PubMed:33886552}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor Fz/Smo family. 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; AC069469; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS19965.1; -. DR PIR; JC5539; JC5539. DR RefSeq; NP_795970.3; NM_176996.4. DR PDB; 6O3C; X-ray; 2.80 A; A=64-566. DR PDBsum; 6O3C; -. DR AlphaFoldDB; P56726; -. DR SMR; P56726; -. DR BioGRID; 235504; 28. DR IntAct; P56726; 17. DR STRING; 10090.ENSMUSP00000001812; -. DR BindingDB; P56726; -. DR ChEMBL; CHEMBL6080; -. DR DrugCentral; P56726; -. DR GuidetoPHARMACOLOGY; 239; -. DR GlyCosmos; P56726; 3 sites, No reported glycans. DR GlyGen; P56726; 3 sites. DR iPTMnet; P56726; -. DR PhosphoSitePlus; P56726; -. DR PaxDb; 10090-ENSMUSP00000001812; -. DR ProteomicsDB; 258703; -. DR ABCD; P56726; 1 sequenced antibody. DR Antibodypedia; 31982; 639 antibodies from 38 providers. DR DNASU; 319757; -. DR Ensembl; ENSMUST00000001812.5; ENSMUSP00000001812.5; ENSMUSG00000001761.8. DR GeneID; 319757; -. DR KEGG; mmu:319757; -. DR UCSC; uc009bef.2; mouse. DR AGR; MGI:108075; -. DR CTD; 6608; -. DR MGI; MGI:108075; Smo. DR VEuPathDB; HostDB:ENSMUSG00000001761; -. DR eggNOG; KOG3577; Eukaryota. DR GeneTree; ENSGT00940000157206; -. DR HOGENOM; CLU_007873_3_1_1; -. DR InParanoid; P56726; -. DR OMA; FLKCTPD; -. DR OrthoDB; 2902735at2759; -. DR PhylomeDB; P56726; -. DR TreeFam; TF106460; -. DR Reactome; R-MMU-5610787; Hedgehog 'off' state. DR Reactome; R-MMU-5620922; BBSome-mediated cargo-targeting to cilium. DR Reactome; R-MMU-5632684; Hedgehog 'on' state. DR Reactome; R-MMU-5635838; Activation of SMO. DR BioGRID-ORCS; 319757; 4 hits in 80 CRISPR screens. DR ChiTaRS; Smo; mouse. DR PRO; PR:P56726; -. DR Proteomes; UP000000589; Chromosome 6. DR RNAct; P56726; Protein. DR Bgee; ENSMUSG00000001761; Expressed in undifferentiated genital tubercle and 104 other cell types or tissues. DR ExpressionAtlas; P56726; baseline and differential. DR GO; GO:0097731; C:9+0 non-motile cilium; IDA:MGI. DR GO; GO:0044295; C:axonal growth cone; ISO:MGI. DR GO; GO:0005901; C:caveola; IEA:Ensembl. DR GO; GO:0005814; C:centriole; IDA:MGI. DR GO; GO:0060170; C:ciliary membrane; IDA:MGI. DR GO; GO:0005929; C:cilium; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0030425; C:dendrite; ISO:MGI. DR GO; GO:0044294; C:dendritic growth cone; ISO:MGI. DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI. DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:MGI. DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0005770; C:late endosome; IDA:MGI. DR GO; GO:0043025; C:neuronal cell body; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0004862; F:cAMP-dependent protein kinase inhibitor activity; ISO:MGI. DR GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW. DR GO; GO:0008142; F:oxysterol binding; IDA:UniProtKB. DR GO; GO:0005113; F:patched binding; ISO:MGI. DR GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0009952; P:anterior/posterior pattern specification; IMP:MGI. DR GO; GO:0006915; P:apoptotic process; IMP:MGI. DR GO; GO:0048143; P:astrocyte activation; IMP:MGI. DR GO; GO:0060413; P:atrial septum morphogenesis; IGI:MGI. DR GO; GO:0048846; P:axon extension involved in axon guidance; ISO:MGI. DR GO; GO:0048468; P:cell development; IMP:MGI. DR GO; GO:0001708; P:cell fate specification; IMP:MGI. DR GO; GO:0008283; P:cell population proliferation; IMP:MGI. DR GO; GO:0071397; P:cellular response to cholesterol; IEP:BHF-UCL. DR GO; GO:0007417; P:central nervous system development; IGI:MGI. DR GO; GO:0021953; P:central nervous system neuron differentiation; IMP:MGI. DR GO; GO:0021696; P:cerebellar cortex morphogenesis; IMP:MGI. DR GO; GO:0021987; P:cerebral cortex development; IMP:MGI. DR GO; GO:0071679; P:commissural neuron axon guidance; ISO:MGI. DR GO; GO:0060242; P:contact inhibition; ISS:UniProtKB. DR GO; GO:0021542; P:dentate gyrus development; IMP:MGI. DR GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; IMP:BHF-UCL. DR GO; GO:0007368; P:determination of left/right symmetry; IMP:MGI. DR GO; GO:0048589; P:developmental growth; IMP:MGI. DR GO; GO:0048565; P:digestive tract development; IMP:MGI. DR GO; GO:0071542; P:dopaminergic neuron differentiation; IMP:MGI. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IMP:MGI. DR GO; GO:0009953; P:dorsal/ventral pattern formation; IMP:MGI. DR GO; GO:0048568; P:embryonic organ development; IGI:MGI. DR GO; GO:0030855; P:epithelial cell differentiation; IMP:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IMP:MGI. DR GO; GO:0060684; P:epithelial-mesenchymal cell signaling; IMP:MGI. DR GO; GO:0048853; P:forebrain morphogenesis; IMP:BHF-UCL. DR GO; GO:0010467; P:gene expression; IDA:MGI. DR GO; GO:0001942; P:hair follicle development; IMP:MGI. DR GO; GO:0031069; P:hair follicle morphogenesis; IMP:MGI. DR GO; GO:0001947; P:heart looping; IMP:BHF-UCL. DR GO; GO:0003007; P:heart morphogenesis; IGI:MGI. DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IDA:MGI. DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI. DR GO; GO:0070986; P:left/right axis specification; IMP:MGI. DR GO; GO:0060644; P:mammary gland epithelial cell differentiation; IMP:MGI. DR GO; GO:0060231; P:mesenchymal to epithelial transition; ISO:MGI. DR GO; GO:0072285; P:mesenchymal to epithelial transition involved in metanephric renal vesicle formation; IMP:UniProtKB. DR GO; GO:0007494; P:midgut development; IMP:BHF-UCL. DR GO; GO:0035264; P:multicellular organism growth; IMP:MGI. DR GO; GO:0051451; P:myoblast migration; IGI:MGI. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:MGI. DR GO; GO:0043392; P:negative regulation of DNA binding; IMP:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IMP:MGI. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB. DR GO; GO:0051799; P:negative regulation of hair follicle development; IMP:MGI. DR GO; GO:2000346; P:negative regulation of hepatocyte proliferation; ISO:MGI. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISO:MGI. DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:MGI. DR GO; GO:0001755; P:neural crest cell migration; IGI:MGI. DR GO; GO:0007405; P:neuroblast proliferation; IGI:MGI. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IMP:MGI. DR GO; GO:0001503; P:ossification; IMP:MGI. DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI. DR GO; GO:0061113; P:pancreas morphogenesis; IMP:MGI. DR GO; GO:0007389; P:pattern specification process; IMP:MGI. DR GO; GO:0010508; P:positive regulation of autophagy; ISO:MGI. DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IMP:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:2000491; P:positive regulation of hepatic stellate cell activation; ISO:MGI. DR GO; GO:0007228; P:positive regulation of hh target transcription factor activity; IMP:BHF-UCL. DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IMP:MGI. DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IMP:CACAO. DR GO; GO:2000179; P:positive regulation of neural precursor cell proliferation; ISO:MGI. DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IGI:MGI. DR GO; GO:0046622; P:positive regulation of organ growth; IMP:CACAO. DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IGI:MGI. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IMP:MGI. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:MGI. DR GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; ISO:MGI. DR GO; GO:0006606; P:protein import into nucleus; IGI:MGI. DR GO; GO:0034504; P:protein localization to nucleus; IMP:MGI. DR GO; GO:0050821; P:protein stabilization; IDA:MGI. DR GO; GO:0010468; P:regulation of gene expression; IGI:MGI. DR GO; GO:2000826; P:regulation of heart morphogenesis; IMP:BHF-UCL. DR GO; GO:0032879; P:regulation of localization; IMP:CACAO. DR GO; GO:1904672; P:regulation of somatic stem cell population maintenance; IMP:MGI. DR GO; GO:0048741; P:skeletal muscle fiber development; IMP:MGI. DR GO; GO:0048745; P:smooth muscle tissue development; IEA:Ensembl. DR GO; GO:0007224; P:smoothened signaling pathway; IDA:MGI. DR GO; GO:0061053; P:somite development; IMP:BHF-UCL. DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IMP:BHF-UCL. DR GO; GO:0021794; P:thalamus development; IMP:MGI. DR GO; GO:0003323; P:type B pancreatic cell development; IMP:MGI. DR GO; GO:0001570; P:vasculogenesis; IMP:MGI. DR GO; GO:0007371; P:ventral midline determination; IMP: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; P56726; MM. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cell projection; Developmental protein; KW Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; KW Phosphoprotein; Receptor; Reference proteome; Signal; Transducer; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..32 FT /evidence="ECO:0000255" FT CHAIN 33..793 FT /note="Protein smoothened" FT /id="PRO_0000013016" FT TOPO_DOM 33..237 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 238..258 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 259..265 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 266..286 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 287..318 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 319..339 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 340..362 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 363..383 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 384..406 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 407..427 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 428..455 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 456..476 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 477..528 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 529..549 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 550..793 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 69..185 FT /note="FZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT REGION 35..61 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 542..573 FT /note="Interaction with BBS5 and BBS7" FT /evidence="ECO:0000269|PubMed:22072986" FT REGION 574..657 FT /note="Required for interaction with PRKACA" FT /evidence="ECO:0000269|PubMed:33886552" FT REGION 585..597 FT /note="Interaction with DLG5" FT /evidence="ECO:0000269|PubMed:25644602" FT REGION 674..703 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 41..55 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 99 FT /ligand="cholesterol" FT /ligand_id="ChEBI:CHEBI:16113" FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT BINDING 398 FT /ligand="cholesterol" FT /ligand_id="ChEBI:CHEBI:16113" FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT MOD_RES 560 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 578 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 594 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 597 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 599 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 642 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 644 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 648 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:33886552" FT MOD_RES 666 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:33886552" FT CARBOHYD 38 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 192 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 497 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 68..182 FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT DISULFID 74..138 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090, FT ECO:0000269|PubMed:31263273, ECO:0007744|PDB:6O3C" FT DISULFID 82..131 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090, FT ECO:0000269|PubMed:31263273, ECO:0007744|PDB:6O3C" FT DISULFID 122..158 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090, FT ECO:0000269|PubMed:31263273, ECO:0007744|PDB:6O3C" FT DISULFID 151..173 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090, FT ECO:0000269|PubMed:31263273, ECO:0007744|PDB:6O3C" FT DISULFID 197..217 FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT DISULFID 221..299 FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT DISULFID 318..394 FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT DISULFID 494..511 FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0007744|PDB:6O3C" FT MUTAGEN 88 FT /note="P->N: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 99 FT /note="D->A: Loss of cholesterol binding and reduced FT SHH-induced activation. No effect on basal signaling." FT /evidence="ECO:0000269|PubMed:35658032" FT MUTAGEN 112..119 FT /note="LWSGLRNA->DYYALKHV: Loss of sterol binding." FT /evidence="ECO:0000269|PubMed:23831757" FT MUTAGEN 112 FT /note="L->A,D: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 112 FT /note="L->D: Loss of sterol binding and reduced response to FT SHH." FT /evidence="ECO:0000269|PubMed:23831757" FT MUTAGEN 113 FT /note="W->Y: Loss of sterol binding and reduced response to FT SHH." FT /evidence="ECO:0000269|PubMed:23831757" FT MUTAGEN 114 FT /note="S->Y: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:23831757" FT MUTAGEN 115 FT /note="G->F: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 116 FT /note="L->A: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 118 FT /note="N->A: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 120 FT /note="P->A,E,G: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 128 FT /note="P->S,E,R: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 134 FT /note="Y->F: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 150 FT /note="L->A,D,S: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 151 FT /note="C->Y: Reduced protein levels, reduced activity and FT loss of localization to cilia." FT /evidence="ECO:0000269|PubMed:19464178" FT MUTAGEN 162 FT /note="E->A: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 165 FT /note="R->A,E: No effect on sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 166 FT /note="G->F: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 168 FT /note="P->A: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 170 FT /note="F->A: Reduced sterol binding." FT /evidence="ECO:0000269|PubMed:24171105" FT MUTAGEN 333 FT /note="V->F: Failure to localize to primary cilia. Loss of FT cholesterol-induced activity." FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0000269|PubMed:35658032" FT MUTAGEN 398 FT /note="Y->F: Remains responsive to SHH and FT 20S-hydroxycholesterol. Reduced basal signaling." FT /evidence="ECO:0000269|PubMed:31263273, FT ECO:0000269|PubMed:35658032" FT MUTAGEN 408 FT /note="V->F: Loss of activity." FT /evidence="ECO:0000269|PubMed:31263273" FT MUTAGEN 412 FT /note="I->F: Loss of activity." FT /evidence="ECO:0000269|PubMed:31263273" FT MUTAGEN 420 FT /note="G->F: Reduced activity in response to SHH." FT /evidence="ECO:0000269|PubMed:31263273" FT MUTAGEN 463 FT /note="A->F: Loss of activity in response to SHH." FT /evidence="ECO:0000269|PubMed:31263273" FT MUTAGEN 470 FT /note="T->Q: Loss of cholesterol-induced activity." FT /evidence="ECO:0000269|PubMed:31263273" FT MUTAGEN 549..550 FT /note="WR->AA: Loss of activity and cilium localization." FT /evidence="ECO:0000269|PubMed:16136078" FT CONFLICT 54 FT /note="D -> N (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT CONFLICT 266 FT /note="Y -> L (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT CONFLICT 690 FT /note="R -> G (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT STRAND 69..71 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 80..82 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 94..96 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 103..113 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 114..117 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 120..133 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 140..144 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 148..152 FT /evidence="ECO:0007829|PDB:6O3C" FT TURN 153..158 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 159..164 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 169..171 FT /evidence="ECO:0007829|PDB:6O3C" FT TURN 175..177 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 185..188 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 201..203 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 207..209 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 217..222 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 228..258 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 260..263 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 266..286 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 287..289 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 293..298 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 303..305 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 308..310 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 312..314 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 317..348 FT /evidence="ECO:0007829|PDB:6O3C" FT TURN 349..351 FT /evidence="ECO:0007829|PDB:6O3C" FT TURN 356..359 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 361..368 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 371..382 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 385..387 FT /evidence="ECO:0007829|PDB:6O3C" FT TURN 389..391 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 393..400 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 403..406 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 409..436 FT /evidence="ECO:0007829|PDB:6O3C" FT STRAND 437..441 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 444..498 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 519..537 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 538..540 FT /evidence="ECO:0007829|PDB:6O3C" FT HELIX 543..554 FT /evidence="ECO:0007829|PDB:6O3C" SQ SEQUENCE 793 AA; 87450 MW; DEAD556A45F7C960 CRC64; MAAGRPVRGP ELAPRRLLQL LLLVLLGGPG RGAALSGNVT GPGPHSASGS SRRDVPVTSP PPPLLSHCGR AAHCEPLRYN VCLGSALPYG ATTTLLAGDS DSQEEAHGKL VLWSGLRNAP RCWAVIQPLL CAVYMPKCEN DRVELPSRTL CQATRGPCAI VERERGWPDF LRCTPDHFPE GCPNEVQNIK FNSSGQCEAP LVRTDNPKSW YEDVEGCGIQ CQNPLFTEAE HQDMHSYIAA FGAVTGLCTL FTLATFVADW RNSNRYPAVI LFYVNACFFV GSIGWLAQFM DGARREIVCR ADGTMRFGEP TSSETLSCVI IFVIVYYALM AGVVWFVVLT YAWHTSFKAL GTTYQPLSGK TSYFHLLTWS LPFVLTVAIL AVAQVDGDSV SGICFVGYKN YRYRAGFVLA PIGLVLIVGG YFLIRGVMTL FSIKSNHPGL LSEKAASKIN ETMLRLGIFG FLAFGFVLIT FSCHFYDFFN QAEWERSFRD YVLCQANVTI GLPTKKPIPD CEIKNRPSLL VEKINLFAMF GTGIAMSTWV WTKATLLIWR RTWCRLTGHS DDEPKRIKKS KMIAKAFSKR RELLQNPGQE LSFSMHTVSH DGPVAGLAFD LNEPSADVSS AWAQHVTKMV ARRGAILPQD VSVTPVATPV PPEEQANMWL VEAEISPELE KRLGRKKKRR KRKKEVCPLR PAPELHHSAP VPATSAVPRL PQLPRQKCLV AANAWGTGES CRQGAWTLVS NPFCPEPSPH QDPFLPGASA PRVWAQGRLQ GLGSIHSRTN LMEAEILDAD SDF //