Protein smoothened

UniProt Q99835 Organism Homo sapiens Gene SMO, SMOH

Also known as: SMO, SMOH

Function

G protein-coupled receptor, which transduces the smoothened signaling pathway. Activated by cholesterol in response to hedgehog (DHH, IHH or SHH) morphogens. In absence of hedgehog, SMO is inactivated by patched protein (PTCH1 or PTCH2), which prevents SMO access to cholesterol. 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. 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. 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. Active SMO also promotes the removal of GPR161, a key inhibitor of the smoothened signaling pathway, from primary cilia (By similarity).

Classification

Family (Pfam): PF01534 Frizzled, PF01392 Fz
InterPro: Frizzled/SFRP, Frizzled/Smoothened_7TM, Frizzled_dom, Frizzled_dom_sf, GPCR_2-like_7TM, SMO_7TM, SMO_CRD
Functional cluster: Mixed Regulatory & Membrane Proteins

Experimental structures · PDB · 15

4JKV X-ray 2.45A
4N4W X-ray 2.80A
4O9R X-ray 3.20A
4QIM X-ray 2.61A
4QIN X-ray 2.60A
5L7D X-ray 3.20A
5L7I X-ray 3.30A
5V56 X-ray 2.90A
5V57 X-ray 3.00A
6OT0 EM 3.90A
6XBJ EM 3.88A
6XBK EM 3.24A
… and 3 more

A predicted model is available from AlphaFold.

Gene Ontology · 45

Disease associations

Curry-Jones syndrome MONDO:0011134

Drugs targeting this protein · 9

GLASDEGIB antagonist
TALADEGIB antagonist
TAK-441 antagonist
LEQ506 antagonist
SONIDEGIB PHOSPHATE inhibitor
BMS-833923 antagonist
GLASDEGIB MALEATE antagonist
VISMODEGIB inhibitor
PATIDEGIB antagonist

Related proteins · sequence + function similarity

Protein smoothened 0.99
Protein smoothened 0.99
Protein smoothened 0.95
Protein smoothened 0.75
Protein smoothened.L 0.71
G protein-coupled receptor family C group 5 member C 0.70
Transmembrane protein 145 0.70
Protein smoothened.S 0.70
Frizzled-4 0.69
G protein-coupled receptor family C group 5 member C 0.68
G protein-coupled receptor family C group 5 member C 0.68
XK-related protein 6 0.68

Co-cited proteins · studied together in the literature

Protein smoothened 1 shared papers
Protein smoothened 6 shared papers
Protein patched homolog 1 2 shared papers
cAMP-dependent protein kinase catalytic subunit alpha 2 shared papers
Dynein regulatory complex subunit 4 1 shared papers
Kinesin-like protein KIF7 1 shared papers
G protein-coupled receptor kinase 2 1 shared papers
Dynein regulatory complex subunit 4 1 shared papers
Transcription activator GLI1 1 shared papers
Dynein regulatory complex subunit 4 1 shared papers
Kinesin-like protein KIF7 1 shared papers
Protein smoothened 1 shared papers

Literature · 18 cited papers

GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade. PLoS Biol. · 2024
A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction. Nat. Struct. Mol. Biol. · 2022
Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain. Sci. Adv. · 2022
Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling. Nat. Chem. Biol. · 2020
Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi. Nature · 2019
Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. Nat. Commun. · 2017
Cholesterol modification of Smoothened is required for hedgehog signaling. Mol. Cell · 2017
Structural basis of Smoothened regulation by its extracellular domains. Nature · 2016
A recurrent mosaic mutation in SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome. Am. J. Hum. Genet. · 2016
Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat. Genet. · 2014
Structure of the human smoothened receptor bound to an antitumour agent. Nature · 2013
A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet. · 2011
… and 6 more in the literature graph

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