Title | Structural basis for the recognition of Sonic Hedgehog by human Patched1. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Gong, X, Qian, H, Cao, P, Zhao, X, Zhou, Q, Lei, J, Yan, N |
Journal | Science |
Date Published | 2018 Jun 28 |
ISSN | 1095-9203 |
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. |
DOI | 10.1126/science.aas8935 |
Alternate Journal | Science |
PubMed ID | 29954986 |