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Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling

Giovanni Luchetti, Ria Sircar, Jennifer H. Kong, Sigrid Nachtergaele, Andreas Sagner, Eamon F. X. Byrne, Douglas F. Covey, Christian Siebold, Rajat Rohatgi
doi: https://doi.org/10.1101/070623
Giovanni Luchetti
1Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, California, United States of America
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Ria Sircar
1Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, California, United States of America
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Jennifer H. Kong
1Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, California, United States of America
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Sigrid Nachtergaele
1Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, California, United States of America
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Andreas Sagner
4The Francis Crick Institute, Mill Hill Laboratory, London, UK
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Eamon F. X. Byrne
2Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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Douglas F. Covey
3Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America
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Christian Siebold
2Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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  • For correspondence: rrohatgi@stanford.edu christian@strubi.strubi.ox.ac.uk
Rajat Rohatgi
1Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, California, United States of America
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  • For correspondence: rrohatgi@stanford.edu christian@strubi.strubi.ox.ac.uk
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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 most 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 21, 2016.
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Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
Giovanni Luchetti, Ria Sircar, Jennifer H. Kong, Sigrid Nachtergaele, Andreas Sagner, Eamon F. X. Byrne, Douglas F. Covey, Christian Siebold, Rajat Rohatgi
bioRxiv 070623; doi: https://doi.org/10.1101/070623
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Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
Giovanni Luchetti, Ria Sircar, Jennifer H. Kong, Sigrid Nachtergaele, Andreas Sagner, Eamon F. X. Byrne, Douglas F. Covey, Christian Siebold, Rajat Rohatgi
bioRxiv 070623; doi: https://doi.org/10.1101/070623

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