SMO
entrez
6608
canonical
uniprot
Q99835
canonical
ensembl
ENSG00000128602
resolver
ensp
ENSP00000249373
resolver
enst
ENST00000249373
resolver
genesymbol
SMO
resolver
genesymbol_syn
SMOH
resolver
hgnc
HGNC:11119
resolver
uniprot
A4D1K5
resolver
uniprot_entry
SMO_HUMAN
resolver
uniprot_sec
A4D1K5
resolver
activity_regulation
ACTIVITY REGULATION: Activated by small molecule TC114, a synthetic ligand (PubMed:28513578). Specifically inhibited by vismodegib, also named Erivedge, an inhibitor of the smoothened signaling pathway used for the treatment of basal-cell carcinoma: vismodegib acts by occluding the cholesterol-binding site (PubMed:27437577). {ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578}.
uniprot
proteins
amino_acid_sequence
MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPPLSHCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWAVIQPLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTNEVQNIKFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAVTGLCTLFTLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGTMRLGEPTSNETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYFHLLTWSLPFVLTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLIRGVMTLFSIKSNHPGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEWERSFRDYVLCQANVTIGLPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVWTKATLLIWRRTWCRLTGQSDDEPKRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPVAGLAFDLNEPSADVSSAWAQHVTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAEISPELQKRLGRKKKRRKRKKEVCPLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWGAGDSCRQGAWTLVSNPFCPEPSPPQDPFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTELMDADSDF
uniprot
proteins
disease_involvement
DISEASE: Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}. Note=The disease is caused by variants affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.
uniprot
proteins
function
FUNCTION: G protein-coupled receptor, which transduces the smoothened signaling pathway (PubMed:19592253, PubMed:27437577, PubMed:28344083, PubMed:31168089, PubMed:32929279, PubMed:36202993). Activated by cholesterol in response to hedgehog (DHH, IHH or SHH) morphogens (PubMed:27437577, PubMed:28344083, PubMed:32929279). In absence of hedgehog, SMO is inactivated by patched protein (PTCH1 or PTCH2), which prevents SMO access to cholesterol (PubMed:28344083). In response to hedgehog-binding to pathched, inhibition is relieved, promoting SMO translocation to primary cilium and activation by cholesterol: cholesterol causes a conformation change that triggers signaling via G protein G(i), mediating inhibition of adenylate cyclase activity and decreassed production of cAMP (PubMed:28344083, PubMed:31168089). Decreased cAMP levels then inhibit protein kinase A (PKA) and promote release of GLI (GLI1, GLI2 and GLI3) transcription factors, which activate expression of target genes (PubMed:31168089). Active SMO also directly inhibits PKA by sequestering its catalytic subunit, PRKACA, at the cell membrane, preventing PRKACA-mediated phosphorylation and subsequent processing of GLI transcription factors (PubMed:36202993, PubMed:39138140). Active SMO also promotes the removal of GPR161, a key inhibitor of the smoothened signaling pathway, from primary cilia (By similarity). {ECO:0000250|UniProtKB:P56726, ECO:0000269|PubMed:19592253, ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28344083, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0000269|PubMed:36202993, ECO:0000269|PubMed:39138140}.
uniprot
proteins
mass_dalton
86397
uniprot
proteins
mutagenesis
MUTAGEN 95; /note="D->N: Abolished cholesterylation and activation; the protein is refractory to activation in response to hedgehog. Abolished ciliary localization."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 97; /note="D->N: Does not affect cholesterylation or ciliary localization."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 108; /note="L->D: Decreased cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 111; /note="G->C: Constitutively active smoothened signaling; when associated with C-496."; /evidence="ECO:0000269|PubMed:32929279"; MUTAGEN 111; /note="G->F: Decreased cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 112; /note="L->A: Abolished cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 116; /note="P->A: Decreased cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 130; /note="Y->F: Abolished cholesterylation. Abolished ciliary localization."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 158; /note="E->A: Decreased cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 162; /note="G->F: Abolished cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 164; /note="P->A: Abolished cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 166; /note="F->A: Abolished cholesterylation."; /evidence="ECO:0000269|PubMed:28344083"; MUTAGEN 329; /note="V->F: Locks SMO in an inactive state. Abolished sterol-binding."; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:32929279"; MUTAGEN 384; /note="D->R: Constitutively active smoothened signaling."; /evidence="ECO:0000269|PubMed:32929279"; MUTAGEN 496; /note="I->C: Constitutively active smoothened signaling; when associated with C-111."; /evidence="ECO:0000269|PubMed:32929279"; MUTAGEN 521; /note="N->A: Decreased smoothened signaling."; /evidence="ECO:0000269|PubMed:31168089"; MUTAGEN 618; /note="W->A: Does not affect ability to sequester PRKACA. Abolished ability to sequester PRKACA; when associated with 628-A-A-629."; /evidence="ECO:0000269|PubMed:36202993"; MUTAGEN 628..629; /note="RR->AA: Decreased ability to sequester PRKACA. Abolished ability to sequester PRKACA; when associated with A-618."; /evidence="ECO:0000269|PubMed:36202993"; MUTAGEN 628; /note="R->A: Does not affect ability to sequester PRKACA."; /evidence="ECO:0000269|PubMed:36202993"; MUTAGEN 629; /note="R->A: Decreased ability to sequester PRKACA."; /evidence="ECO:0000269|PubMed:36202993
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by GRK2 and/GRK3 kinases promotes interaction with protein kinase A catalytic subunit PRKACA. {ECO:0000269|PubMed:39138140}.
uniprot
proteins
protein_family
G protein-coupled receptor Fz/Smo family
uniprot
proteins
pubmed
12690205
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
19592253
uniprot
proteins
pubmed
21659505
uniprot
proteins
pubmed
22072986
uniprot
proteins
pubmed
23636324
uniprot
proteins
pubmed
24859340
uniprot
proteins
pubmed
27236920
uniprot
proteins
pubmed
27437577
uniprot
proteins
pubmed
28344083
uniprot
proteins
pubmed
28513578
uniprot
proteins
pubmed
31168089
uniprot
proteins
pubmed
32929279
uniprot
proteins
pubmed
35658032
uniprot
proteins
pubmed
36202993
uniprot
proteins
pubmed
39138140
uniprot
proteins
pubmed
8906787
uniprot
proteins
pubmed
9422511
uniprot
proteins
sequence_length
787
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P56726}; Multi-pass membrane protein {ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279}. Cell projection, cilium membrane {ECO:0000269|PubMed:22072986, ECO:0000269|PubMed:28344083}; Multi-pass membrane protein {ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279}. Note=Translocates to primary cilium in response to hedgehog (DHH, IHH or SHH) morphogens (By similarity). Cilium localization is mediated via a beta-arrestin and KIF3A-dependent mechanism (By similarity). {ECO:0000250|UniProtKB:P56726}.
uniprot
proteins
transmembrane_region
TRANSMEM 230..253; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 265..282; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 315..337; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 358..378; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 399..420; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 453..474; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM"; TRANSMEM 516..537; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:27437577, ECO:0000269|PubMed:28513578, ECO:0000269|PubMed:31168089, ECO:0000269|PubMed:32929279, ECO:0007744|PDB:5L7D, ECO:0007744|PDB:5V56, ECO:0007744|PDB:5V57, ECO:0007744|PDB:6OT0, ECO:0007744|PDB:6XBJ, ECO:0007744|PDB:6XBK, ECO:0007744|PDB:6XBL, ECO:0007744|PDB:6XBM
uniprot
proteins