9.A.14.16.4
G-protein homologue, Smoothed; Smo; Smoh, of 787 aas and 7 TMSs (Lum and Beachy 2004). It is regulated via the Hedgehog pathway by the RND-like protein, Patched1 ((PTCH1; TC# 2.A.6.6.13) (Myers et al. 2017). The cryoEM structure of SMO bound to Patched reveals that SMO has a channel open to the membrane as well as to the extracellular cysteine-rich domain (CRD). This domain, like that in Patched, is large enough to accomodate cholesterol, so SMO could be a transporter as well as a receptor (Sommer and Lemmon 2018; Qi et al. 2018). Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling (Qi et al. 2020). SMO, a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7 TMSs) of SMO. Qi et al. 2020 determined the structures of SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in the 7-TMSs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMSs to CRD. Additional structures of two gain-of-function variants, SMO(D384R) and SMO(G111C/I496C), showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMSs, thereby activating SMO. Thus, sterol transport through the core of SMO is a major regulator of SMO-mediated signaling. These observations shows that like other 7 TMS GPCRs, SMO is capable of transport, in this case, transporting cholesterol (Qi et al. 2020). The regulatory activities of cellular lipids and sterols has been measured during Hedgehog signaling (Deshpande and Manglik 2022).