Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling
The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2013-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/01340 |
| _version_ | 1811180501366472704 |
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| author | Sigrid Nachtergaele Daniel M Whalen Laurel K Mydock Zhonghua Zhao Tomas Malinauskas Kathiresan Krishnan Philip W Ingham Douglas F Covey Christian Siebold Rajat Rohatgi |
| author_facet | Sigrid Nachtergaele Daniel M Whalen Laurel K Mydock Zhonghua Zhao Tomas Malinauskas Kathiresan Krishnan Philip W Ingham Douglas F Covey Christian Siebold Rajat Rohatgi |
| author_sort | Sigrid Nachtergaele |
| collection | DOAJ |
| description | The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. |
| first_indexed | 2024-04-11T09:04:17Z |
| format | Article |
| id | doaj.art-d808c19bbead4fb1b641ef3237212563 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:04:17Z |
| publishDate | 2013-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d808c19bbead4fb1b641ef32372125632022-12-22T04:32:41ZengeLife Sciences Publications LtdeLife2050-084X2013-10-01210.7554/eLife.01340Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signalingSigrid Nachtergaele0Daniel M Whalen1Laurel K Mydock2Zhonghua Zhao3Tomas Malinauskas4Kathiresan Krishnan5Philip W Ingham6Douglas F Covey7Christian Siebold8Rajat Rohatgi9Department of Biochemistry, Stanford University School of Medicine, Stanford, United StatesDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, United StatesA*STAR Institute of Molecular and Cell Biology, Singapore, SingaporeDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, United StatesA*STAR Institute of Molecular and Cell Biology, Singapore, Singapore; Lee Kong Chian School of Medicine, Imperial College London/Nanyang Technological University, Singapore, SingaporeDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, United StatesDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Biochemistry, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Stanford University School of Medicine, Stanford, United StatesThe Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants.https://elifesciences.org/articles/01340Hedgehog signalingoxysterolsmoothenedcysteine rich domain |
| spellingShingle | Sigrid Nachtergaele Daniel M Whalen Laurel K Mydock Zhonghua Zhao Tomas Malinauskas Kathiresan Krishnan Philip W Ingham Douglas F Covey Christian Siebold Rajat Rohatgi Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling eLife Hedgehog signaling oxysterol smoothened cysteine rich domain |
| title | Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling |
| title_full | Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling |
| title_fullStr | Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling |
| title_full_unstemmed | Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling |
| title_short | Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling |
| title_sort | structure and function of the smoothened extracellular domain in vertebrate hedgehog signaling |
| topic | Hedgehog signaling oxysterol smoothened cysteine rich domain |
| url | https://elifesciences.org/articles/01340 |
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