Smoothened stimulation by membrane sterols drives Hedgehog pathway activity

Deshpande, Ishan; Liang, Jiahao; Hedeen, Danielle; Roberts, Kelsey J.; Zhang, Yunxiao; Ha, Betty; Latorraca, Naomi R.; Faust, Bryan; Dror, Ron O.; Beachy, Philip A.; Myers, Benjamin R.; Manglik, Aashish

doi:10.1038/s41586-019-1355-4

Title: Smoothened stimulation by membrane sterols drives Hedgehog pathway activity

Journal Article · Mon Jul 01 00:00:00 EDT 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-1355-4· OSTI ID:1574163

Deshpande, Ishan ^[1]; Liang, Jiahao ^[1]; Hedeen, Danielle ^[2]; Roberts, Kelsey J. ^[3]; Zhang, Yunxiao ^[3]; Ha, Betty ^[3]; Latorraca, Naomi R. ^[3]; Faust, Bryan ^[1]; Dror, Ron O. ^[3]; Beachy, Philip A. ^[3]; Myers, Benjamin R. ^[4]; Manglik, Aashish ^[5]

Univ. of California, San Francisco, CA (United States)
Univ. of Utah, Salt Lake City, UT (United States)
Stanford Univ., CA (United States)
Univ. of Utah, Salt Lake City, UT (United States); Stanford Univ., CA (United States)
Stanford Univ., CA (United States); Univ. of California, San Francisco, CA (United States)

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma. Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models, a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. Overall, these results—combined with signalling studies and molecular dynamics simulations—delineate the structural basis for PTCH1–SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; DP50D023048; R01GM127359; R01GM102498; ACB-12002; AGM-12006; 1S10OD012289–01A1

OSTI ID:: 1574163

Journal Information:: Nature (London), Vol. 571, Issue 7764; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 102 works

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References (62)

Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma Yauch, R. L.; Dijkgraaf, G. J. P.; Alicke, B. Science, Vol. 326, Issue 5952 https://doi.org/10.1126/science.1179386	journal	September 2009
Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling Nedelcu, Daniel; Liu, Jing; Xu, Yangqing Nature Chemical Biology, Vol. 9, Issue 9 https://doi.org/10.1038/nchembio.1290	journal	July 2013
Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched Zhang, Yunxiao; Bulkley, David P.; Xin, Yao Cell, Vol. 175, Issue 5 https://doi.org/10.1016/j.cell.2018.10.026	journal	November 2018
Screening and large-scale expression of membrane proteins in mammalian cells for structural studies Goehring, April; Lee, Chia-Hsueh; Wang, Kevin H. Nature Protocols, Vol. 9, Issue 11 https://doi.org/10.1038/nprot.2014.173	journal	October 2014
Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand Zhang, Xianjun; Zhao, Fei; Wu, Yiran Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15383	journal	May 2017
Structural basis of Smoothened regulation by its extracellular domains Byrne, Eamon F. X.; Sircar, Ria; Miller, Paul S. Nature, Vol. 535, Issue 7613 https://doi.org/10.1038/nature18934	journal	July 2016
A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis Cooper, Michael K.; Wassif, Christopher A.; Krakowiak, Patrycja A. Nature Genetics, Vol. 33, Issue 4 https://doi.org/10.1038/ng1134	journal	March 2003
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
Structural basis for the recognition of Sonic Hedgehog by human Patched1 Gong, Xin; Qian, Hongwu; Cao, Pingping Science, Vol. 361, Issue 6402 https://doi.org/10.1126/science.aas8935	journal	June 2018
Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine Taipale, Jussi; Chen, James K.; Cooper, Michael K. Nature, Vol. 406, Issue 6799 https://doi.org/10.1038/35023008	journal	August 2000
Small molecule modulation of Smoothened activity Chen, J. K.; Taipale, J.; Young, K. E. Proceedings of the National Academy of Sciences, Vol. 99, Issue 22 https://doi.org/10.1073/pnas.182542899	journal	October 2002
Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald Salomon-Ferrer, Romelia; Götz, Andreas W.; Poole, Duncan Journal of Chemical Theory and Computation, Vol. 9, Issue 9 https://doi.org/10.1021/ct400314y	journal	August 2013
A general strategy for the evolution of bond-forming enzymes using yeast display Chen, I.; Dorr, B. M.; Liu, D. R. Proceedings of the National Academy of Sciences, Vol. 108, Issue 28 https://doi.org/10.1073/pnas.1101046108	journal	June 2011
Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process Rohatgi, R.; Milenkovic, L.; Corcoran, R. B. Proceedings of the National Academy of Sciences, Vol. 106, Issue 9 https://doi.org/10.1073/pnas.0813373106	journal	February 2009
Structural Basis of Smoothened Activation in Hedgehog Signaling Huang, Pengxiang; Zheng, Sanduo; Wierbowski, Bradley M. Cell, Vol. 174, Issue 2 https://doi.org/10.1016/j.cell.2018.04.029	journal	July 2018
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins ^† MacKerell, A. D.; Bashford, D.; Bellott, M. The Journal of Physical Chemistry B, Vol. 102, Issue 18 https://doi.org/10.1021/jp973084f	journal	April 1998
Improving FRET dynamic range with bright green and red fluorescent proteins Lam, Amy J.; St-Pierre, François; Gong, Yiyang Nature Methods, Vol. 9, Issue 10 https://doi.org/10.1038/nmeth.2171	journal	September 2012
Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling Huang, Pengxiang; Nedelcu, Daniel; Watanabe, Miyako Cell, Vol. 166, Issue 5 https://doi.org/10.1016/j.cell.2016.08.003	journal	August 2016
Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened Chen, J. K. Genes & Development, Vol. 16, Issue 21 https://doi.org/10.1101/gad.1025302	journal	November 2002
Alteration of the Myometrial Plasma Membrane Cholesterol Content with .beta.-Cyclodextrin Modulates the Binding Affinity of the Oxytocin Receptor Klein, Uwe; Gimpl, Gerald; Fahrenholz, Falk Biochemistry, Vol. 34, Issue 42 https://doi.org/10.1021/bi00042a009	journal	October 1995
Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma Sharpe, Hayley J.; Pau, Gregoire; Dijkgraaf, Gerrit J. Cancer Cell, Vol. 27, Issue 3 https://doi.org/10.1016/j.ccell.2015.02.001	journal	March 2015
Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma Buonamici, S.; Williams, J.; Morrissey, M. Science Translational Medicine, Vol. 2, Issue 51 https://doi.org/10.1126/scitranslmed.3001599	journal	September 2010
Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma Atwood, Scott X.; Sarin, Kavita Y.; Whitson, Ramon J. Cancer Cell, Vol. 27, Issue 3 https://doi.org/10.1016/j.ccell.2015.02.002	journal	March 2015
Crystallizing membrane proteins using lipidic mesophases Caffrey, Martin; Cherezov, Vadim Nature Protocols, Vol. 4, Issue 5 https://doi.org/10.1038/nprot.2009.31	journal	April 2009
Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody Ring, Aaron M.; Manglik, Aashish; Kruse, Andrew C. Nature, Vol. 502, Issue 7472 https://doi.org/10.1038/nature12572	journal	September 2013
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Emerging structural biology of lipid G protein-coupled receptors: Structural Biology of Lipid G Protein-Coupled Receptors Audet, Martin; Stevens, Raymond C. Protein Science, Vol. 28, Issue 2 https://doi.org/10.1002/pro.3509	journal	January 2019
Improved Treatment of the Protein Backbone in Empirical Force Fields MacKerell, Alexander D.; Feig, Michael; Brooks, Charles L. Journal of the American Chemical Society, Vol. 126, Issue 3 https://doi.org/10.1021/ja036959e	journal	January 2004
Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling Luchetti, Giovanni; Sircar, Ria; Kong, Jennifer H. eLife, Vol. 5 https://doi.org/10.7554/eLife.20304	journal	October 2016
Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning Hopkins, Chad W.; Le Grand, Scott; Walker, Ross C. Journal of Chemical Theory and Computation, Vol. 11, Issue 4 https://doi.org/10.1021/ct5010406	journal	March 2015
Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium Myers, Benjamin R.; Neahring, Lila; Zhang, Yunxiao Proceedings of the National Academy of Sciences, Vol. 114, Issue 52 https://doi.org/10.1073/pnas.1717891115	journal	December 2017
A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein Rodriguez, Erik A.; Tran, Geraldine N.; Gross, Larry A. Nature Methods, Vol. 13, Issue 9 https://doi.org/10.1038/nmeth.3935	journal	August 2016
Small Molecule Inhibition of GDC-0449 Refractory Smoothened Mutants and Downstream Mechanisms of Drug Resistance Dijkgraaf, Gerrit J. P.; Alicke, Bruno; Weinmann, Lasse Cancer Research, Vol. 71, Issue 2 https://doi.org/10.1158/0008-5472.CAN-10-2876	journal	December 2010
Yeast surface display platform for rapid discovery of conformationally selective nanobodies McMahon, Conor; Baier, Alexander S.; Pascolutti, Roberta Nature Structural & Molecular Biology, Vol. 25, Issue 3 https://doi.org/10.1038/s41594-018-0028-6	journal	February 2018
Hedgehog Signaling: From Basic Biology to Cancer Therapy Wu, Fujia; Zhang, Yu; Sun, Bo Cell Chemical Biology, Vol. 24, Issue 3 https://doi.org/10.1016/j.chembiol.2017.02.010	journal	March 2017
Structural Basis for G Protein-Coupled Receptor Activation Manglik, Aashish; Kruse, Andrew C. Biochemistry, Vol. 56, Issue 42 https://doi.org/10.1021/acs.biochem.7b00747	journal	September 2017
Multiple ligand binding sites regulate the Hedgehog signal transducer Smoothened in vertebrates Byrne, Eamon FX; Luchetti, Giovanni; Rohatgi, Rajat Current Opinion in Cell Biology, Vol. 51 https://doi.org/10.1016/j.ceb.2017.10.004	journal	April 2018
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ ₁ and χ ₂ Dihedral Angles Best, Robert B.; Zhu, Xiao; Shim, Jihyun Journal of Chemical Theory and Computation, Vol. 8, Issue 9 https://doi.org/10.1021/ct300400x	journal	August 2012
Patched acts catalytically to suppress the activity of Smoothened Taipale, J.; Cooper, M. K.; Maiti, T. Nature, Vol. 418, Issue 6900 https://doi.org/10.1038/nature00989	journal	August 2002
Structures of human Patched and its complex with native palmitoylated sonic hedgehog Qi, Xiaofeng; Schmiege, Philip; Coutavas, Elias Nature, Vol. 560, Issue 7716 https://doi.org/10.1038/s41586-018-0308-7	journal	July 2018
Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs Wang, Chong; Wu, Huixian; Evron, Tama Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms5355	journal	July 2014
Converse Conformational Control of Smoothened Activity by Structurally Related Small Molecules Yang, Hongbo; Xiang, Jing; Wang, Nengdong Journal of Biological Chemistry, Vol. 284, Issue 31 https://doi.org/10.1074/jbc.M807648200	journal	April 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Reduced cholesterol levels impair Smoothened activation in Smith–Lemli–Opitz syndrome Blassberg, Robert; Macrae, James I.; Briscoe, James Human Molecular Genetics, Vol. 25, Issue 4 https://doi.org/10.1093/hmg/ddv507	journal	December 2015
Nanobodies to Study G Protein–Coupled Receptor Structure and Function Manglik, Aashish; Kobilka, Brian K.; Steyaert, Jan Annual Review of Pharmacology and Toxicology, Vol. 57, Issue 1 https://doi.org/10.1146/annurev-pharmtox-010716-104710	journal	January 2017
Structural insights into µ-opioid receptor activation Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A. J. Nature, Vol. 524, Issue 7565 https://doi.org/10.1038/nature14886	journal	August 2015
Cilia-Associated Oxysterols Activate Smoothened Raleigh, David R.; Sever, Navdar; Choksi, Pervinder K. Molecular Cell, Vol. 72, Issue 2 https://doi.org/10.1016/j.molcel.2018.08.034	journal	October 2018
Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response Myers, Benjamin R.; Sever, Navdar; Chong, Yong Chun Developmental Cell, Vol. 26, Issue 4 https://doi.org/10.1016/j.devcel.2013.07.015	journal	August 2013
Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling Ayers, Katie L.; Thérond, Pascal P. Trends in Cell Biology, Vol. 20, Issue 5 https://doi.org/10.1016/j.tcb.2010.02.002	journal	May 2010
Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling Nachtergaele, Sigrid; Whalen, Daniel M.; Mydock, Laurel K. eLife, Vol. 2 https://doi.org/10.7554/eLife.01340	journal	October 2013
CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate–Protein Modeling Guvench, Olgun; Mallajosyula, Sairam S.; Raman, E. Prabhu Journal of Chemical Theory and Computation, Vol. 7, Issue 10 https://doi.org/10.1021/ct200328p	journal	August 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data Roe, Daniel R.; Cheatham, Thomas E. Journal of Chemical Theory and Computation, Vol. 9, Issue 7 https://doi.org/10.1021/ct400341p	journal	June 2013
The mechanisms of Hedgehog signalling and its roles in development and disease Briscoe, James; Thérond, Pascal P. Nature Reviews Molecular Cell Biology, Vol. 14, Issue 7 https://doi.org/10.1038/nrm3598	journal	May 2013
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-13641-0	journal	December 2019
Mechanism of pore opening in the calcium-activated chloride channel TMEM16A Lam, Andy K. M.; Dutzler, Raimund Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-020-20788-8	journal	February 2021
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Structural Basis of Smoothened Activation in Hedgehog Signaling Huang, Pengxiang; Zheng, Sanduo; Wierbowski, Bradley M. Cell, Vol. 175, Issue 1 https://doi.org/10.1016/j.cell.2018.09.003	journal	September 2018
Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs Xi-Ping, Huang,; J., Urban, Dan; G., Caron, Marc The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/kvmf-ds60	text	January 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

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Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype Infante, Paola; Alfonsi, Romina; Ingallina, Cinzia Cell Death & Disease, Vol. 7, Issue 9 https://doi.org/10.1038/cddis.2016.195	journal	September 2016
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Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy Ikeda, Sadakatsu; Goodman, Aaron M.; Cohen, Philip R. npj Genomic Medicine, Vol. 1, Issue 1 https://doi.org/10.1038/npjgenmed.2016.37	journal	October 2016
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Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer Xie, Hao; Paradise, Brooke D.; Ma, Wen Wee Cells, Vol. 8, Issue 5 https://doi.org/10.3390/cells8050394	journal	April 2019
Cross-Talk between Wnt and Hh Signaling Pathways in the Pathology of Basal Cell Carcinoma Noubissi, Felicite; Yedjou, Clement; Spiegelman, Vladimir International Journal of Environmental Research and Public Health, Vol. 15, Issue 7 https://doi.org/10.3390/ijerph15071442	journal	July 2018
Hedgehog Signaling Pathway and Autophagy in Cancer Zeng, Xian; Ju, Dianwen International Journal of Molecular Sciences, Vol. 19, Issue 8 https://doi.org/10.3390/ijms19082279	journal	August 2018
Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients Giannopoulou, Aikaterini; Konstantakou, Eumorphia; Velentzas, Athanassios International Journal of Molecular Sciences, Vol. 20, Issue 4 https://doi.org/10.3390/ijms20040937	journal	February 2019
Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer Abe, Yoshinori; Tanaka, Nobuyuki Journal of Developmental Biology, Vol. 5, Issue 4 https://doi.org/10.3390/jdb5040012	journal	November 2017

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