RT Journal Article
T1 Structural basis for catalyzed assembly of the Sonic hedgehog–Patched1 signaling complex
A1 García Linares, Sara
A1 Huang, Pengxiang
A1 Wierbowski, Bradley M.
A1 Lian, Tengfei
A1 Chan, Charlene
A1 Jiang, Jiansen
A1 Salic, Adrian
AB 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 can-cer. 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 fashionand 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
PB Cell Press
YR 2022
FD 2022-03-14
LK https://hdl.handle.net/20.500.14352/130425
UL https://hdl.handle.net/20.500.14352/130425
LA eng
NO Pengxiang Huang, Bradley M. Wierbowski, Tengfei Lian, Charlene Chan, Sara García-Linares, Jiansen Jiang, Adrian Salic, Structural basis for catalyzed assembly of the Sonic hedgehog–Patched1 signaling complex, Developmental Cell, Volume 57, Issue 5, 2022, Pages 670-685.e8, ISSN 1534-5807, https://doi.org/10.1016/j.devcel.2022.02.008. (https://www.sciencedirect.com/science/article/pii/S1534580722000740)
DS Docta Complutense
RD 19 ene 2026