Structural basis of sterol recognition by human hedgehog receptor PTCH1
The hedgehog receptor Patched-1 (PTCH1) plays a key role in the hedgehog signaling pathway as a putative cholesterol transporter. A recent paper in Science Advances by the Korkhov (IBC & PSI) and Wutz groups (IMHS) provides clues for understanding the structural basis of PTCH1-sterol interactions.
The hedgehog signaling pathway has an important role in tissue patterning during embryonic development and is linked to human disease. Binding of Sonic hedgehog morphogen, Shh, to PTCH1 initiates the hedgehog signaling cascade. PTCH1 has been suggested to act as a transporter for cholesterol, and this transport activity apparently underlies its role in controlling the hedgehog pathway. The Korkhov group determined the 3.4 Å resolution structure of PTCH1 bound to a hedgehog ligand variant ShhNC24II using cryo-EM and single particle analysis. The high quality of the cryo-EM data allowed the authors to observe a belt of sterol molecules bound at the protein-lipid interface. Interestingly, a set of sterols was observed bound in positions within the outer and inner leaflet of the membrane at the Sterol Sensing Domain (SSD) and the SSD-like domain of PTCH1. The structure suggests a possible route for sterol translocation across the lipid bilayer mediated by PTCH1 and related transporters.
Link to the publication in external page Science Advances