IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27257-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27257-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27257-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Hongwen Chen & Xiaofeng Qi & Rebecca A. Faulkner & Marc M. Schumacher & Linda M. Donnelly & Russell A. DeBose-Boyd & Xiaochun Li, 2022. "Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Samuel C. Griffiths & Rebekka A. Schwab & Kamel El Omari & Benjamin Bishop & Ellen J. Iverson & Tomas Malinauskas & Ramin Dubey & Mingxing Qian & Douglas F. Covey & Robert J. C. Gilbert & Rajat Rohatg, 2021. "Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Roman Vetter & Dagmar Iber, 2022. "Precision of morphogen gradients in neural tube development," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Megan Lo & Amnon Sharir & Michael D. Paul & Hayarpi Torosyan & Christopher Agnew & Amy Li & Cynthia Neben & Pauline Marangoni & Libin Xu & David R. Raleigh & Natalia Jura & Ophir D. Klein, 2022. "CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Alina Ornik-Cha & Julia Wilhelm & Jessica Kobylka & Hanno Sjuts & Attilio V. Vargiu & Giuliano Malloci & Julian Reitz & Anja Seybert & Achilleas S. Frangakis & Klaas M. Pos, 2021. "Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Adrian On Wah Leung & Andrew Chung Hin Poon & Xue Wang & Chen Feng & Peikai Chen & Zhengfan Zheng & Michael KaiTsun To & Wilson Cheuk Wing Chan & Martin Cheung & Danny Chan, 2024. "Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Jody L. Andersen & Gui-Xin He & Prathusha Kakarla & Ranjana KC & Sanath Kumar & Wazir Singh Lakra & Mun Mun Mukherjee & Indrika Ranaweera & Ugina Shrestha & Thuy Tran & Manuel F. Varela, 2015. "Multidrug Efflux Pumps from Enterobacteriaceae, Vibrio cholerae and Staphylococcus aureus Bacterial Food Pathogens," IJERPH, MDPI, vol. 12(2), pages 1-61, January.
    8. Yidan Xu & Guowen Jia & Tingting Li & Zixuan Zhou & Yitian Luo & Yulin Chao & Juan Bao & Zhaoming Su & Qianhui Qu & Dianfan Li, 2022. "Molecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27257-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.