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TitleStructural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.
Journal, issue, pagesDev Cell, Vol. 57, Issue 5, Page 670-685.e8, Year 2022
Publish dateFeb 25, 2022
AuthorsPengxiang Huang / Bradley M Wierbowski / Tengfei Lian / Charlene Chan / Sara García-Linares / Jiansen Jiang / Adrian Salic /
PubMed AbstractThe dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1) to activate the Hedgehog pathway, which is fundamental in development and ...The dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1) to activate the Hedgehog pathway, which is fundamental in development and cancer. SHH engagement with PTCH1 requires the GAS1 coreceptor, but the mechanism is unknown. We demonstrate a unique role for GAS1, catalyzing SHH-PTCH1 complex assembly in vertebrate cells by direct SHH transfer from the extracellular SCUBE2 carrier to PTCH1. Structure of the GAS1-SHH-PTCH1 transition state identifies how GAS1 recognizes the SHH palmitate and cholesterol modifications in modular fashion and how it facilitates lipid-dependent SHH handoff to PTCH1. Structure-guided experiments elucidate SHH movement from SCUBE2 to PTCH1, explain disease mutations, and demonstrate that SHH-induced PTCH1 dimerization causes its internalization from the cell surface. These results define how the signaling-competent SHH-PTCH1 complex assembles, the key step triggering the Hedgehog pathway, and provide a paradigm for understanding morphogen reception and its regulation.
External linksDev Cell / PubMed:35231446 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.53 Å
Structure data

24466

7rhq

EMDB-24466, PDB-7rhq:
Cryo-EM structure of Xenopus Patched-1 in complex with GAS1 and Sonic Hedgehog
Method: EM (single particle) / Resolution: 3.53 Å

24467

7rhr

EMDB-24467, PDB-7rhr:
Cryo-EM structure of Xenopus Patched-1 in nanodisc
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

Source
  • homo sapiens (human)
  • xenopus laevis (African clawed frog)
  • xenopus calcaratus (Biafran clawed frog)
KeywordsMEMBRANE PROTEIN / GPCR / complex / patched

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