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Cell. 2018 Nov 15;175(5):1352-1364.e14. doi: 10.1016/j.cell.2018.10.026. Epub 2018 Nov 8.

Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94158, USA.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
4
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: wcho@uic.edu.
7
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: yifan.cheng@ucsf.edu.
8
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94158, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Biochemistry and Urology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: pbeachy@stanford.edu.

Abstract

Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity of the 7-transmembrane protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of the Patched protein reveals striking transmembrane domain similarities to prokaryotic RND transporters. A central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting Patched activity in cholesterol transport. Cholesterol activity in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability.

KEYWORDS:

Hedgehog; Hedgehog signaling; Patched; RND transporter; Smoothened; cholesterol sensor; cholesterol transport; cryo-EM; membrane lipid asymmetry

PMID:
30415841
PMCID:
PMC6326742
DOI:
10.1016/j.cell.2018.10.026
[Indexed for MEDLINE]
Free PMC Article

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