Structural basis for the recognition of Sonic Hedgehog by human Patched1.

TitleStructural basis for the recognition of Sonic Hedgehog by human Patched1.
Publication TypeJournal Article
Year of Publication2018
AuthorsGong, X, Qian, H, Cao, P, Zhao, X, Zhou, Q, Lei, J, Yan, N
JournalScience
Date Published2018 Jun 28
ISSN1095-9203
Abstract

The Hedgehog (Hh) pathway involved in development and regeneration is activated by the extracellular binding of Hh to the membrane receptor Patched (Ptch). We report the cryo-EM structures of human Ptch1 alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 Å and 3.6 Å, respectively. Ptch1 comprises two interacting extracellular domains ECD1 and ECD2 and twelve transmembrane segments (TMs), with TMs 2-6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2, and the other on the membrane-facing cavity of SSD. Structure-guided mutational analysis shows that interaction between ShhN and Ptch1 is steroid-dependent. The structure of a steroid binding-deficient Ptch1 mutant displays pronounced conformational rearrangements.

DOI10.1126/science.aas8935
Alternate JournalScience
PubMed ID29954986