TY - JOUR
T1 - Structural basis for the recognition of Sonic Hedgehog by human Patched1
AU - Gong, Xin
AU - Qian, Hongwu
AU - Cao, Pingping
AU - Zhao, Xin
AU - Zhou, Qiang
AU - Lei, Jianlin
AU - Yan, Nieng
N1 - Funding Information:
Supported by National Key Basic Research (973) Program grant 2015CB910101 (N.Y.) and National Key R&D Program grants 2016YFA0500402 (N.Y.) and 2016YFA0501100 (J.L.) from Ministry of Science and Technology of China; National Natural Science Foundation of China projects 31621092, 31630017, and 31611130036 (N.Y.); and the Shirley M. Tilghman endowed professorship from Princeton University (N.Y.). We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology.
Publisher Copyright:
© 2017 The Authors.
PY - 2018/8/10
Y1 - 2018/8/10
N2 - 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 structures of human Ptch1 alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 and 3.6 angstroms, respectively, as determined by cryo–electron microscopy. Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the 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.
AB - 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 structures of human Ptch1 alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 and 3.6 angstroms, respectively, as determined by cryo–electron microscopy. Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the 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.
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U2 - 10.1126/science.aas8935
DO - 10.1126/science.aas8935
M3 - Article
C2 - 29954986
AN - SCOPUS:85049249797
SN - 0036-8075
VL - 361
JO - Science
JF - Science
IS - 6402
M1 - eaas8935
ER -