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Application of Electrophysiology Measurement to Study the Activity of Electro-Neutral Transporters
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Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched

Yunxiao Zhang1, David P Bulkley2, Yao Xin3

  • 1Institute 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.

Cell
|November 13, 2018
PubMed

Insights

Patched (PTCH1) protein regulates Smoothened activity by controlling cholesterol availability, impacting Hedgehog signaling and basal cell carcinoma development. This suggests a novel role for PTCH1 in cholesterol transport.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Structural biology

Background:

  • Hedgehog (Hh) proteins are crucial for tissue development and maintenance.
  • Patched (PTCH1) is a 12-transmembrane receptor that inhibits Smoothened (SMO), a key component of the Hh pathway.
  • Loss of PTCH1 function is linked to basal cell carcinoma (BCC).

Purpose of the Study:

  • To elucidate the structural basis of PTCH1 function.
  • To investigate the relationship between PTCH1, SMO, and cholesterol.
  • To understand PTCH1's role in Hh pathway regulation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine PTCH1 structure.
  • Analysis of transmembrane domain similarities to RND transporters.
  • Investigation of cholesterol activity in response to PTCH1 and Hh stimulation.

Main Results:

  • PTCH1 shares structural similarities with prokaryotic RND transporters, featuring a hydrophobic conduit.
  • This conduit contains cholesterol-like molecules, suggesting a role in cholesterol transport.
  • PTCH1 expression reduces plasma membrane cholesterol, which is restored by Hh signaling.

Conclusions:

  • PTCH1 may function as a cholesterol transporter.
  • PTCH1 regulates SMO activity by modulating cholesterol availability at the plasma membrane.
  • This mechanism provides new insights into Hh pathway regulation and BCC pathogenesis.
Keywords:
HedgehogHedgehog signalingPatchedRND transporterSmoothenedcholesterol sensorcholesterol transportcryo-EMmembrane lipid asymmetry

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