Details

Autor(en) / Beteiligte

• Hoppe, Nicholas
• Harrison, Simone
• Hwang, Sun-Hee
• Chen, Ziwei
• Karelina, Masha
• Deshpande, Ishan
• Suomivuori, Carl-Mikael
• Palicharla, Vivek R
• Berry, Samuel P
• Tschaikner, Philipp
• Regele, Dominik
• Covey, Douglas F
• Stefan, Eduard
• Marks, Debora S
• Reiter, Jeremy F
• Dror, Ron O
• Evers, Alex S
• Mukhopadhyay, Saikat
• Manglik, Aashish

Titel

GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway

Ist Teil von

• Nature structural & molecular biology, 2024-04, Vol.31 (4), p.667

Ort / Verlag

United States

Erscheinungsjahr

2024

Link zum Volltext

Beschreibungen/Notizen

• The orphan G protein-coupled receptor (GPCR) GPR161 plays a central role in development by suppressing Hedgehog signaling. The fundamental basis of how GPR161 is activated remains unclear. Here, we determined a cryogenic-electron microscopy structure of active human GPR161 bound to heterotrimeric G . This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, a sterol that binds adjacent to transmembrane helices 6 and 7 stabilizes a GPR161 conformation required for G coupling. Mutations that prevent sterol binding to GPR161 suppress G -mediated signaling. These mutants retain the ability to suppress GLI2 transcription factor accumulation in primary cilia, a key function of ciliary GPR161. By contrast, a protein kinase A-binding site in the GPR161 C terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the role of GPR161 function in other signaling pathways.