SMO
Domain
The N-terminal extracellular domain mediates sterol-binding which is required for maximal activation of signaling (PubMed:24859340). Contains a second sterol-binding site within the seven-transmembrane pocket which is also required for activation (By similarity). The activating sterol is likely to be cholesterol (PubMed:35658032). The extracellular site is required for SHH-induced activity while the site within the transmembrane pocket regulates basal signaling in the absence of SHH (PubMed:35658032).
Function
G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling. Binding of sonic hedgehog (SHH) to its receptor patched prevents inhibition of smoothened (SMO) by patched. When active, SMO binds to and sequesters protein kinase A catalytic subunit PRKACA at the cell membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors which releases the GLI proteins from PRKACA-mediated inhibition and allows for transcriptional activation of hedgehog pathway target genes (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity).
Involvement in disease
Curry-Jones syndrome
CRJS
A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas.
None
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).
Post-translational modifications
Phosphorylation by GRK kinases is required for interaction with protein kinase A catalytic subunit PRKACA.
Sequence Similarities
Belongs to the G-protein coupled receptor Fz/Smo family.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Cell projection
- Cilium
- Cilium localization is promoted by SHH and is required for activity.
Alternative names
SMOH, SMO, Protein smoothened, Protein Gx