title: Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling.
abstract: 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.
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.|Department of Medicine, Stanford University School of Medicine, Stanford, United States.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Luchetti
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.|Department of Medicine, Stanford University School of Medicine, Stanford, United States.
authors.forename: Ria
authors.initials: R
authors.lastname: Sircar
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.|Department of Medicine, Stanford University School of Medicine, Stanford, United States.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Kong
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.|Department of Medicine, Stanford University School of Medicine, Stanford, United States.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nachtergaele
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sagner
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Eamon Fx
authors.initials: EF
authors.lastname: Byrne
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0002-6635-3621
authors.initials: C
authors.lastname: Siebold
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.|Department of Medicine, Stanford University School of Medicine, Stanford, United States.
authors.forename: Rajat
authors.identifier: http://orcid.org/0000-0001-7609-8858
authors.initials: R
authors.lastname: Rohatgi
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D006364:Hedgehogs / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000819:agonists*
chemical_list: D000072086:Smoothened Receptor; D002784:Cholesterol
keywords: G-protein coupled receptor; biochemistry; cholesterol; developmental biology; hedgehog signaling; human; mouse; stem cells