Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex
- Science. 2018 Oct 5;362(6410):eaas8843. doi: 10.1126/science.aas8843.
- 1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
- 2. Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065, USA.
- 3. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. [email protected].
- 4. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Aberrant Hedgehog (HH) signaling leads to various types of Cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.