7E2I

Cryo-EM structure of hDisp1NNN-ShhN

Summary for 7E2I

• Entry DOI: 10.2210/pdb7e2i/pdb
• Related: 7E2G 7E2H
• EMDB information: 30956 30957 30958
• Descriptor: Sonic hedgehog protein, Protein dispatched homolog 1, ZINC ION, ... (5 entities in total)
• Functional Keywords: membrane protein, lipid transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 225143.59

Authors

Li, W.,Wang, L.,Gong, X. (deposition date: 2021-02-05, release date: 2021-12-08, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (4.07 Å)