Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Qi, X; Schmiege, P; Coutavas, E; Li, X

Published Date

  • October 5, 2018

Published In

Volume / Issue

  • 362 / 6410

PubMed ID

  • 30139912

Pubmed Central ID

  • 30139912

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.aas8843

Language

  • eng

Conference Location

  • United States