Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.

TitleInhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.
Publication TypeJournal Article
Year of Publication2019
AuthorsQian, H, Cao, P, Hu, M, Gao, S, Yan, N, Gong, X
JournalNat Commun
Date Published2019 May 24
KeywordsCholesterol, Cryoelectron Microscopy, Hedgehog Proteins, HEK293 Cells, Humans, Ligands, Lipoylation, Models, Molecular, Patched-1 Receptor, Protein Binding, Protein Domains, Protein Multimerization, Recombinant Proteins

<p>The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhN) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhN through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhN and the other through the Ca-mediated interface on ShhN. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.</p>

Alternate JournalNat Commun
PubMed ID31127104
PubMed Central IDPMC6534611