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

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  • Wanqiu Li

    (Southern University of Science and Technology
    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
    Shenzhen University Health Science Center)

  • Peiyi Wang

    (Southern University of Science and Technology)

  • Adrian Salic

    (Harvard Medical School)

  • Xin Gong

    (Southern University of Science and Technology)

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.

Suggested Citation

  • Wanqiu Li & Linlin Wang & Bradley M. Wierbowski & Mo Lu & Feitong Dong & Wenchen Liu & Sisi Li & Peiyi Wang & Adrian Salic & Xin Gong, 2021. "Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27257-w
    DOI: 10.1038/s41467-021-27257-w
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    References listed on IDEAS

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    1. Xiaofeng Qi & Philip Schmiege & Elias Coutavas & Jiawei Wang & Xiaochun Li, 2018. "Structures of human Patched and its complex with native palmitoylated sonic hedgehog," Nature, Nature, vol. 560(7716), pages 128-132, August.
    2. Jason S. McLellan & Xiaoyan Zheng & Glenn Hauk & Rodolfo Ghirlando & Philip A. Beachy & Daniel J. Leahy, 2008. "The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla," Nature, Nature, vol. 455(7215), pages 979-983, October.
    3. Tao Long & Xiaofeng Qi & Abdirahman Hassan & Qiren Liang & Jef K. De Brabander & Xiaochun Li, 2020. "Structural basis for itraconazole-mediated NPC1 inhibition," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Hongwu Qian & Pingping Cao & Miaohui Hu & Shuai Gao & Nieng Yan & Xin Gong, 2019. "Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    5. Satoshi Murakami & Ryosuke Nakashima & Eiki Yamashita & Akihito Yamaguchi, 2002. "Crystal structure of bacterial multidrug efflux transporter AcrB," Nature, Nature, vol. 419(6907), pages 587-593, October.
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