7e2g | pdb_00007e2g

Cryo-EM structure of hDisp1NNN-3C

spinqualitylabelsall models 7e2g, resolution 3.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.61Å Ligands: NAG, Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.,Li W, Wang L, Wierbowski BM, Lu M, Dong F, Liu W, Li S, Wang P, Salic A, Gong X Nat Commun. 2021 Nov 29;12(1):6966. doi: 10.1038/s41467-021-27257-w. PMID:34845226 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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