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황선희Sun-Hee Hwang

University of Texas Southwestern Medical Center

Nat. Struct. Mol. Biol., Feb 07 2024, | https://doi.org/10.1038/s41594-024-01223-8 GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway

Nicholas Hoppe^1,2,19, Simone Harrison^1,2,19, Sun-Hee Hwang^3,19, Ziwei Chen^4,5, Masha Karelina ^6,7,8,9,10, Ishan Deshpande1, Carl-Mikael Suomivuori^7,8,9,10, Vivek R. Palicharla³, Samuel P. Berry ¹¹, Philipp Tschaikner^12,13, Dominik Regele¹², Douglas F. Covey^4,5,14,15, Eduard Stefan ^12,13, Debora S. Marks¹¹, Jeremy F. Reiter^16,17, Ron O. Dror ^6,7,8,9,10, Alex S. Evers ^4,5,15, Saikat Mukhopadhyay³ & Aashish Manglik^1,17,18

¹Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.

²Biophysics Graduate Program, University of California, San Francisco, CA, USA.

³Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

⁴Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.

⁵Taylor Institute for Innovative Psychiatric Research, St Louis, MO, USA.

⁶Biophysics Program, Stanford University, Stanford, CA, USA.

⁷Department of Computer Science, Stanford University, Stanford, CA, USA.

⁸Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

⁹Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.

¹⁰Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.

¹¹Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

¹²Institute of Molecular Biology and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.

¹³Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria.

¹⁴Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.

¹⁵Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.

¹⁶Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

¹⁷Chan Zuckerberg Biohub, San Francisco, CA, USA.

¹⁸Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.

¹⁹These authors contributed equally: Nicholas Hoppe, Simone Harrison, Sun-Hee Hwang.

Corresponding authors

Correspondence to Saikat Mukhopadhyay or Aashish Manglik.

Abstract

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 _s. 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 _s coupling. Mutations that prevent sterol binding to GPR161 suppress G _s-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.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-19)
연구진국외 연구진
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