title: Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response.
abstract: Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo) by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine-rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs.
authors: Department of Biochemistry, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Benjamin R
authors: BR
authors: Myers
authors: Navdar
authors: N
authors: Sever
authors: Yong Chun
authors: YC
authors: Chong
authors: James
authors: J
authors: Kim
authors: Jitendra D
authors: JD
authors: Belani
authors: Scott
authors: S
authors: Rychnovsky
authors: J Fernando
authors: JF
authors: Bazan
authors: Philip A
authors: PA
authors: Beachy
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D051157:Frizzled Receptors; D053823:Hedgehog Proteins; D008024:Ligands; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D013261:Sterols; D051153:Wnt Proteins
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