7E2I

Cryo-EM structure of hDisp1NNN-ShhN

7E2I の概要

• エントリーDOI: 10.2210/pdb7e2i/pdb
• 関連するPDBエントリー: 7E2G 7E2H
• EMDBエントリー: 30956 30957 30958
• 分子名称: Sonic hedgehog protein, Protein dispatched homolog 1, ZINC ION, ... (5 entities in total)
• 機能のキーワード: membrane protein, lipid transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 225143.59

構造登録者

Li, W.,Wang, L.,Gong, X. (登録日: 2021-02-05, 公開日: 2021-12-08, 最終更新日: 2025-06-18)

主引用文献

Li, W.,Wang, L.,Wierbowski, B.M.,Lu, M.,Dong, F.,Liu, W.,Li, S.,Wang, P.,Salic, A.,Gong, X.
Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.
Nat Commun, 12:6966-6966, 2021

PubMed Abstract: The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1-Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters.

PubMed: 34845226
DOI: 10.1038/s41467-021-27257-w

実験手法

ELECTRON MICROSCOPY (4.07 Å)