Structure of human Dispatched-1 provides insights into Hedgehog ligand biogenesis

Life Sci Alliance. 2020 Jul 9;3(8):e202000776. doi: 10.26508/lsa.202000776. Print 2020 Aug.

Abstract

Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM structure of human DISP1 protein. DISP1 contains 12 transmembrane helices (TMs) and two extracellular domains (ECDs). Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Moreover, several cholesterol-like molecules are found in the TMs, implying a transport-like function of DISP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Hedgehog Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / ultrastructure*
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / ultrastructure*
  • Niemann-Pick C1 Protein
  • Patched-1 Receptor / metabolism
  • Patched-1 Receptor / ultrastructure
  • Protein Domains / genetics
  • Signal Transduction
  • Trans-Activators / genetics

Substances

  • DISP1 protein, human
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Membrane Transport Proteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • PTCH1 protein, human
  • Patched-1 Receptor
  • Trans-Activators
  • dispatched-1 protein, mouse

Associated data

  • PDB/6OEU
  • PDB/5U74
  • PDB/6E1H
  • PDB/6TD6
  • PDB/6XE6