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Cholesterol access in cellular membranes controls Hedgehog signaling
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Journal Article
Cholesterol access in cellular membranes controls Hedgehog signaling
2020
Overview
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.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Chemistry and Materials Science
/ Drosophila melanogaster - genetics
/ Drosophila melanogaster - metabolism
/ Epithelial Cells - chemistry
/ Epithelial Cells - metabolism
/ Hedgehog Proteins - chemistry
/ Hedgehog Proteins - genetics
/ Hedgehog Proteins - metabolism
/ Humans
/ Kinases
/ Ligands
/ Patched-1 Receptor - chemistry
/ Patched-1 Receptor - genetics
/ Patched-1 Receptor - metabolism
/ Protein Conformation, alpha-Helical
/ Protein Conformation, beta-Strand
/ Protein Interaction Domains and Motifs
/ Proteins
/ Smoothened Receptor - chemistry
