Article

Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling

Department of Biochemistry , Stanford University School of Medicine , Stanford , United States.
eLife Sciences (Impact Factor: 9.32). 10/2013; 2(2):e01340. DOI: 10.7554/eLife.01340
Source: PubMed

ABSTRACT

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. DOI:http://dx.doi.org/10.7554/eLife.01340.001.

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    • "Most of these drugs target a membrane protein called Smoothened. Now, in eLife, Rajat Rohatgi at Stanford University School of Medicine and co-workers in the US, UK and Singapore—including Sigrid Nachtergaele (Stanford) and Daniel Whalen (Oxford) as joint first authors—provide new insights into the regulation of Smoothened by oxysterols, a class of naturally occurring compounds, and suggest new options for the pharmacological modulation of Hedgehog signalling (Nachtergaele et al., 2013). Similar results have also been reported in Nature Chemical Biology by Daniel Nedelcu of Harvard Medical School and co-workers (Nedelcu et al., 2013), and in Developmental Cell by Benjamin Myers of Stanford University School of Medicine and co-workers (Myers et al., 2013). "
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    ABSTRACT: Oxysterols modulate the Hedgehog signalling pathway by binding a novel site on the membrane protein Smoothened, which may offer new options for the treatment of cancers linked to this pathway.
    Full-text · Article · Dec 2013 · eLife Sciences
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    ABSTRACT: The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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    [Show abstract] [Hide abstract]
    ABSTRACT: The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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