TCDB is operated by the Saier Lab Bioinformatics Group
« See all members of the family


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).    

Accession Number:Q99835
Protein Name:Smoothened homolog
Length:787
Molecular Weight:86397.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:8
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate

Cross database links:

Structure:
4JKV   4N4W   4O9R   4QIM   4QIN   5L7D   5L7I   5V56   5V57   6OT0   [...more]

External Searches:

Analyze:

Predict TMSs (Predict number of transmembrane segments)
Window Size: Angle:  
FASTA formatted sequence
1:	MAAARPARGP ELPLLGLLLL LLLGDPGRGA ASSGNATGPG PRSAGGSARR SAAVTGPPPP 
61:	LSHCGRAAPC EPLRYNVCLG SVLPYGATST LLAGDSDSQE EAHGKLVLWS GLRNAPRCWA 
121:	VIQPLLCAVY MPKCENDRVE LPSRTLCQAT RGPCAIVERE RGWPDFLRCT PDRFPEGCTN 
181:	EVQNIKFNSS GQCEVPLVRT DNPKSWYEDV EGCGIQCQNP LFTEAEHQDM HSYIAAFGAV 
241:	TGLCTLFTLA TFVADWRNSN RYPAVILFYV NACFFVGSIG WLAQFMDGAR REIVCRADGT 
301:	MRLGEPTSNE TLSCVIIFVI VYYALMAGVV WFVVLTYAWH TSFKALGTTY QPLSGKTSYF 
361:	HLLTWSLPFV LTVAILAVAQ VDGDSVSGIC FVGYKNYRYR AGFVLAPIGL VLIVGGYFLI 
421:	RGVMTLFSIK SNHPGLLSEK AASKINETML RLGIFGFLAF GFVLITFSCH FYDFFNQAEW 
481:	ERSFRDYVLC QANVTIGLPT KQPIPDCEIK NRPSLLVEKI NLFAMFGTGI AMSTWVWTKA 
541:	TLLIWRRTWC RLTGQSDDEP KRIKKSKMIA KAFSKRHELL QNPGQELSFS MHTVSHDGPV 
601:	AGLAFDLNEP SADVSSAWAQ HVTKMVARRG AILPQDISVT PVATPVPPEE QANLWLVEAE 
661:	ISPELQKRLG RKKKRRKRKK EVCPLAPPPE LHPPAPAPST IPRLPQLPRQ KCLVAAGAWG 
721:	AGDSCRQGAW TLVSNPFCPE PSPPQDPFLP SAPAPVAWAH GRRQGLGPIH SRTNLMDTEL 
781:	MDADSDF