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Cell
2016 Aug 25;1665:1176-1187.e14. doi: 10.1016/j.cell.2016.08.003.
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Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling.
Huang P
,
Nedelcu D
,
Watanabe M
,
Jao C
,
Kim Y
,
Liu J
,
Salic A
.
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In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and is unique among CRD-containing receptors. We demonstrate that Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol.
Aanstad,
The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling.
2009, Pubmed
Aanstad,
The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling.
2009,
Pubmed
Alcedo,
The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal.
1996,
Pubmed
Bazan,
Structural ties between cholesterol transport and morphogen signaling.
2009,
Pubmed
Braberg,
SALIGN: a web server for alignment of multiple protein sequences and structures.
2012,
Pubmed
Carroll,
Sterol synthesis. Synthesis of 3 beta-hydroxy-25,26,26,26,27,27,27-heptafluorocholest-5-en-7-one and its effects on HMG-CoA reductase activity in Chinese hamster ovary cells, on ACAT activity in rat jejunal microsomes, and serum cholesterol levels in rats.
1998,
Pubmed
Chen,
Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
2002,
Pubmed
Chen,
Small molecule modulation of Smoothened activity.
2002,
Pubmed
Cooper,
A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis.
2003,
Pubmed
Corbit,
Vertebrate Smoothened functions at the primary cilium.
2005,
Pubmed
Corcoran,
Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells.
2006,
Pubmed
Dijkgraaf,
Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance.
2011,
Pubmed
Dorn,
A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia.
2012,
Pubmed
Dwyer,
Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells.
2007,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Frank-Kamenetsky,
Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
2002,
Pubmed
Gimpl,
Expression of the human oxytocin receptor in baculovirus-infected insect cells: high-affinity binding is induced by a cholesterol-cyclodextrin complex.
1995,
Pubmed
Greenfield,
Using circular dichroism spectra to estimate protein secondary structure.
2006,
Pubmed
Ingham,
Hedgehog signaling in animal development: paradigms and principles.
2001,
Pubmed
Janda,
Structural basis of Wnt recognition by Frizzled.
2012,
Pubmed
,
Xenbase
Jao,
Bioorthogonal probes for imaging sterols in cells.
2015,
Pubmed
Kim,
20(S)-hydroxycholesterol inhibits PPARgamma expression and adipogenic differentiation of bone marrow stromal cells through a hedgehog-dependent mechanism.
2007,
Pubmed
Kruse,
Activation and allosteric modulation of a muscarinic acetylcholine receptor.
2013,
Pubmed
Lum,
The Hedgehog response network: sensors, switches, and routers.
2004,
Pubmed
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Minor,
HKL-3000: the integration of data reduction and structure solution--from diffraction images to an initial model in minutes.
2006,
Pubmed
Murakami,
Crystal structures of a multidrug transporter reveal a functionally rotating mechanism.
2006,
Pubmed
Murone,
Sonic hedgehog signaling by the patched-smoothened receptor complex.
1999,
Pubmed
Myers,
Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response.
2013,
Pubmed
Nachtergaele,
Oxysterols are allosteric activators of the oncoprotein Smoothened.
2012,
Pubmed
Nachtergaele,
Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.
2013,
Pubmed
Nakano,
A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched.
1989,
Pubmed
Nedelcu,
Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling.
2013,
Pubmed
,
Xenbase
Rohatgi,
Patched1 regulates hedgehog signaling at the primary cilium.
2007,
Pubmed
Sinha,
Purmorphamine activates the Hedgehog pathway by targeting Smoothened.
2006,
Pubmed
Taipale,
Patched acts catalytically to suppress the activity of Smoothened.
2002,
Pubmed
Taipale,
Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.
2000,
Pubmed
Tseng,
The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins.
1999,
Pubmed
Tukachinsky,
A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.
2010,
Pubmed
Tukachinsky,
Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.
2012,
Pubmed
Voss,
3V: cavity, channel and cleft volume calculator and extractor.
2010,
Pubmed
Wang,
Structure of the human smoothened receptor bound to an antitumour agent.
2013,
Pubmed
Xie,
Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.
1999,
Pubmed
Yauch,
Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
2009,
Pubmed
van den Heuvel,
smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.
1996,
Pubmed