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Structures of human Patched and its complex with native palmitoylated sonic hedgehog.

Publication ,  Journal Article
Qi, X; Schmiege, P; Coutavas, E; Wang, J; Li, X
Published in: Nature
August 2018

Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4-6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH-N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2018

Volume

560

Issue

7716

Start / End Page

128 / 132

Location

England

Related Subject Headings

  • Protein Domains
  • Patched-1 Receptor
  • Palmitic Acid
  • Models, Molecular
  • Lipoylation
  • Ligands
  • Humans
  • Hedgehog Proteins
  • General Science & Technology
  • Fatty Acids
 

Citation

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Qi, X., Schmiege, P., Coutavas, E., Wang, J., & Li, X. (2018). Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature, 560(7716), 128–132. https://doi.org/10.1038/s41586-018-0308-7
Qi, Xiaofeng, Philip Schmiege, Elias Coutavas, Jiawei Wang, and Xiaochun Li. “Structures of human Patched and its complex with native palmitoylated sonic hedgehog.Nature 560, no. 7716 (August 2018): 128–32. https://doi.org/10.1038/s41586-018-0308-7.
Qi X, Schmiege P, Coutavas E, Wang J, Li X. Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature. 2018 Aug;560(7716):128–32.
Qi, Xiaofeng, et al. “Structures of human Patched and its complex with native palmitoylated sonic hedgehog.Nature, vol. 560, no. 7716, Aug. 2018, pp. 128–32. Pubmed, doi:10.1038/s41586-018-0308-7.
Qi X, Schmiege P, Coutavas E, Wang J, Li X. Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature. 2018 Aug;560(7716):128–132.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2018

Volume

560

Issue

7716

Start / End Page

128 / 132

Location

England

Related Subject Headings

  • Protein Domains
  • Patched-1 Receptor
  • Palmitic Acid
  • Models, Molecular
  • Lipoylation
  • Ligands
  • Humans
  • Hedgehog Proteins
  • General Science & Technology
  • Fatty Acids