7RHQ

Cryo-EM structure of Xenopus Patched-1 in complex with GAS1 and Sonic Hedgehog

7RHQ の概要

• エントリーDOI: 10.2210/pdb7rhq/pdb
• 関連するPDBエントリー: 7RHR
• EMDBエントリー: 24466
• 分子名称: Patched-1, PALMITIC ACID, Sonic hedgehog protein N-product, ... (10 entities in total)
• 機能のキーワード: gpcr, complex, membrane protein
• 由来する生物種: Xenopus laevis (African clawed frog); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 188925.72

構造登録者

Huang, P.,Lian, T.,Wierbowski, B.,Garcia-Linares, S.,Jiang, J.,Salic, A. (登録日: 2021-07-18, 公開日: 2022-03-02, 最終更新日: 2024-10-23)

主引用文献

Huang, P.,Wierbowski, B.M.,Lian, T.,Chan, C.,Garcia-Linares, S.,Jiang, J.,Salic, A.
Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.
Dev.Cell, 57:670-685.e8, 2022

PubMed Abstract: 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.

PubMed: 35231446
DOI: 10.1016/j.devcel.2022.02.008

実験手法

ELECTRON MICROSCOPY (3.53 Å)