Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling
Giovanni Luchetti,
Ria Sircar,
Jennifer H Kong,
Sigrid Nachtergaele,
Andreas Sagner,
Eamon FX Byrne,
Douglas F Covey,
Christian Siebold,
Rajat Rohatgi
Affiliations
Giovanni Luchetti
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United States
Ria Sircar
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United States
Jennifer H Kong
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United States
Sigrid Nachtergaele
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United States
Andreas Sagner
Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
Eamon FX Byrne
Division of Structural Biology, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Douglas F Covey
Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States
Division of Structural Biology, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United States
Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike many GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.
