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Cryo-EM structure of the hedgehog release protein dispatched


Cannac, Fabien; Qi, Chao; Falschlunger, Julia; Hausmann, George; Basler, Konrad; Korkhov, Volodymyr M (2020). Cryo-EM structure of the hedgehog release protein dispatched. Science Advances, 6(16):eaay7928.

Abstract

The Hedgehog (Hh) signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In <jats:italic>Drosophila melanogaster</jats:italic>, the pathway is primed by secretion of a dually lipid-modified morphogen, Hh, a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has, so far, not been described. Here, we describe a cryo–electron microscopy structure of the <jats:italic>D. melanogaster</jats:italic> Dispatched at 3.2-Å resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A three-dimensional reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.

Abstract

The Hedgehog (Hh) signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In <jats:italic>Drosophila melanogaster</jats:italic>, the pathway is primed by secretion of a dually lipid-modified morphogen, Hh, a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has, so far, not been described. Here, we describe a cryo–electron microscopy structure of the <jats:italic>D. melanogaster</jats:italic> Dispatched at 3.2-Å resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A three-dimensional reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Multidisciplinary
Language:English
Date:1 April 2020
Deposited On:11 Aug 2020 14:57
Last Modified:12 Aug 2020 20:00
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1126/sciadv.aay7928
PubMed ID:32494603
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_176992
  • : Project TitleStructural molecular biology of membrane proteins in signal transduction and cholesterol recognition
  • : FunderSNSF
  • : Grant IDPP00P3_150665
  • : Project TitleStructural molecular biology of membrane proteins in signal transduction and cholesterol recognition

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