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Nature. 2018 Aug;560(7716):128-132. doi: 10.1038/s41586-018-0308-7. Epub 2018 Jul 11.

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

Author information

1
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Laboratory of Cell Biology, The Rockefeller University, New York, NY, USA.
3
State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, China. jwwang@tsinghua.edu.cn.
4
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochun.li@utsouthwestern.edu.
5
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochun.li@utsouthwestern.edu.

Abstract

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.

PMID:
29995851
PMCID:
PMC6341490
DOI:
10.1038/s41586-018-0308-7
[Indexed for MEDLINE]
Free PMC Article

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