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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.

Original publication

DOI

10.1038/s41589-020-00678-2

Type

Journal article

Journal

Nature chemical biology

Publication Date

12/2020

Volume

16

Pages

1303 - 1313

Addresses

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. arun.radhakrishnan@utsouthwestern.edu.

Keywords

Cell Membrane, Cilia, Epithelial Cells, Animals, Humans, Drosophila melanogaster, Cholesterol, Signal Transduction, Gene Expression Regulation, Protein Binding, Hedgehog Proteins, Protein Interaction Domains and Motifs, Patched-1 Receptor, Smoothened Receptor, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand