Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 12, Pages 1303-1313Publisher
NATURE RESEARCH
DOI: 10.1038/s41589-020-00678-2
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Funding
- Cancer Research UK [C20724/A26752]
- European Research Council [647278]
- National Institutes of Health [GM118082, GM106078]
- NIH [HL20948]
- Welch Foundation [I-1793]
- Leducq Foundation [19CVD04]
- European Research Council (ERC) [647278] Funding Source: European Research Council (ERC)
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The Hedgehog (Hh) receptor PTCH1 uses its transporter-like function to inhibit the GPCR SMO by limiting the pool of accessible membrane cholesterol. Cholesterol acts as a ligand for SMO to activate downstream signaling. The Hedgehog (Hh) signaling pathway coordinates cell-cell communication in development and regeneration. Defects in this pathway underlie diseases ranging from birth defects to cancer. Hh signals are transmitted across the plasma membrane by two proteins, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1, a transporter-like tumor-suppressor protein, binds to Hh ligands, but SMO, a G-protein-coupled-receptor family oncoprotein, transmits the Hh signal across the membrane. Recent structural, biochemical and cell-biological studies have converged at the surprising model that a specific pool of plasma membrane cholesterol, termed accessible cholesterol, functions as a second messenger that conveys the signal between PTCH1 and SMO. Beyond solving a central puzzle in Hh signaling, these studies are revealing new principles in membrane biology: how proteins respond to and remodel cholesterol accessibility in membranes and how the cholesterol composition of organelle membranes is used to regulate protein function.
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