Journal: Nat Commun / Year: 2021 Title: Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release. Authors: Wanqiu Li / Linlin Wang / Bradley M Wierbowski / Mo Lu / Feitong Dong / Wenchen Liu / Sisi Li / Peiyi Wang / Adrian Salic / Xin Gong / 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- ...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.
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Feb 5, 2021
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Dec 8, 2021
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Dec 8, 2021
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Dec 8, 2021
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Dec 8, 2021
Processing site: PDBj / Status: Released
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