Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.

ABSTRACT: Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration¹. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma². Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and l

SUBMITTER: Deshpande I 

PROVIDER: S-EPMC6709672 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature