Unknown

Dataset Information

0

Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.


ABSTRACT: Smoothened (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-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we 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 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMOD384R and SMOG111C/I496C, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.

SUBMITTER: Qi X 

PROVIDER: S-EPMC7669734 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.

Qi Xiaofeng X   Friedberg Lucas L   De Bose-Boyd Ryan R   Long Tao T   Li Xiaochun X  

Nature chemical biology 20200914 12


Smoothened (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-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-G<sub>i</sub> complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S  ...[more]

Similar Datasets

| S-EPMC6709672 | biostudies-literature
| S-EPMC4321822 | biostudies-literature
| S-EPMC3526344 | biostudies-literature
| S-EPMC5035717 | biostudies-literature
| S-EPMC6046275 | biostudies-literature
| S-EPMC4319017 | biostudies-literature
| S-EPMC7337509 | biostudies-literature
| S-EPMC6597826 | biostudies-literature
| S-EPMC2945252 | biostudies-literature
| S-EPMC7923671 | biostudies-literature