The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling
Open accessAbstract
Summary 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 unique among CRD-containing receptors. We demonstrate 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.
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Cites
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Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Phaser crystallographic software
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Vertebrate Smoothened functions at the primary cilium
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Patched1 Regulates Hedgehog Signaling at the Primary Cilium
Rohatgi, R., Milenkovic, L., & Scott, M. P. (2007) · Science · doi:10.1126/science.1139740 · Cited by 1,426
Patched acts catalytically to suppress the activity of Smoothened
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BackgroundA Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia
Dorn, K. V., Hughes, C. E., & Rohatgi, R. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.07.004 · Cited by 174
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Metadata
- Authors
- Huang, P., Nedelcu, D., Watanabe, M., Jao, C., Kim, Y., Liu, J., & Salic, A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 166
- Issue
- 5
- Pages
- 1176-1187.e14
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2509291718
- Cited by
- 377
- References
- 6
- FWCI
- 18.96
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Huang, P., Nedelcu, D., Watanabe, M., Jao, C., Kim, Y., Liu, J., & Salic, A. (2016). Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling. Cell. https://doi.org/10.1016/j.cell.2016.08.003
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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