Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release

Wanqiu Li, Linlin Wang, Bradley M. Wierbowski, Mo Lu, Feitong Dong, Wenchen Liu, Sisi Li, Peiyi Wang, Adrian Salic () and Xin Gong ()
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Wanqiu Li: Southern University of Science and Technology
Linlin Wang: Southern University of Science and Technology
Bradley M. Wierbowski: Harvard Medical School
Mo Lu: Southern University of Science and Technology
Feitong Dong: Southern University of Science and Technology
Wenchen Liu: Southern University of Science and Technology
Sisi Li: Southern University of Science and Technology
Peiyi Wang: Southern University of Science and Technology
Adrian Salic: Harvard Medical School
Xin Gong: Southern University of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27257-w

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