Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
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...
| Hoofdauteurs: | , , , , , , , , |
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| Formaat: | Journal article |
| Taal: | English |
| Gepubliceerd in: |
eLife Sciences Publications
2016
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| _version_ | 1826269819690811392 |
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| author | Luchetti, G Sircar, R Kong, J Nachtergaele, S Sagner, A Byrne, E Covey, D Siebold, C Rohatgi, R |
| author_facet | Luchetti, G Sircar, R Kong, J Nachtergaele, S Sagner, A Byrne, E Covey, D Siebold, C Rohatgi, R |
| author_sort | Luchetti, G |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:31:07Z |
| format | Journal article |
| id | oxford-uuid:44b7a7c4-3383-4e8c-b92f-a800d08a8aec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:31:07Z |
| publishDate | 2016 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:44b7a7c4-3383-4e8c-b92f-a800d08a8aec2022-03-26T15:03:17ZCholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signalingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:44b7a7c4-3383-4e8c-b92f-a800d08a8aecEnglishSymplectic Elements at OxfordeLife Sciences Publications2016Luchetti, GSircar, RKong, JNachtergaele, SSagner, AByrne, ECovey, DSiebold, CRohatgi, RCholesterol 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. |
| spellingShingle | Luchetti, G Sircar, R Kong, J Nachtergaele, S Sagner, A Byrne, E Covey, D Siebold, C Rohatgi, R Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title | Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title_full | Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title_fullStr | Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title_full_unstemmed | Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title_short | Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling |
| title_sort | cholesterol activates the g protein coupled receptor smoothened to promote morphogenetic signaling |
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