Structures of human Patched and its complex with native palmitoylated sonic hedgehog
Open accessAbstract
Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms 1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers 2,4-6. 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) protein 7. 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-receptors 8. 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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Solved structures of PTCH1 bound or unbound to SHH and SMO bound or unbound to cholesterol derivatives reveal important insights into SMO regulation.
“However, the solved structures of PTCH1 bound or unbound to SHH 111, 112 and SMO bound or unbound to cholesterol derivatives 113 reveal important insights.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [113]
Binding of cholesterol to the extracellular cysteine-rich domain of SMO dramatically changes the conformation of this domain relative to the transmembrane domains, leading to release of the π-cation lock.
“Binding of cholesterol to the extracellular cysteine rich domain of SMO dramatically changes the conformation of this domain with respect to the transmembrane domains, leading to release of the π-cation lock.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [113]
The paper’s structural discussion (page unavailable) concerns Patched-1 and its complex with Sonic Hedgehog, not a cholesterol-bound SMO structure. Searches for SMO’s cysteine-rich domain, its movement relative to the transmembrane domains, and a π-cation lock found no passage addressing the claimed mechanism. (LLM, conf=0.76)
Experimental — accuracy not yet measuredA longitudinal tunnel capable of accommodating cholesterol was identified in the transmembrane region of active SMO, suggesting that SMO itself might move cholesterol from the plasma membrane to the extracellular domain.
“Interestingly, a longitudinal tunnel capable of accommodating cholesterol was identified in the transmembrane region of active SMO, suggesting that SMO itself might move cholesterol from the plasma membrane to the extracellular domain 113.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [113]
The passage describing a hydrophobic pocket (section labeled Abstract; page unavailable) locates it in Ptch1, not active SMO. A further passage says the mechanism of SMO inhibition remains poorly understood. Searches for a longitudinal tunnel in SMO and cholesterol movement through SMO found no passage addressing either claim in our copy. (LLM, conf=0.78)
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- Authors
- Qi, X., Schmiege, P., Coutavas, E., Wang, J., & Li, X.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Rockefeller University (US)
- State Key Laboratory of Membrane Biology (CN)
- Corresponding author
- Wang, Jiawei
- Li, Xiaochun
- Venue
- Nature
- Published
- 2018-07-11
- Volume
- 560
- Issue
- 7716
- Pages
- 128-132
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6341490
- OpenAlex
- W2859185793
- Cited by
- 178
- References
- 47
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 12 · 2023: 15 · 2022: 19 · 2021: 43 · 2020: 34 · 2019: 29 · 2018: 11
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas
- University of Texas Southwestern Medical Center
- National Heart, Lung, and Blood Institute (P01HL020948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Patched1, PTCH1, Sonic hedgehog, Hedgehog signaling, palmitoylation, N-terminal domain, protein structure, ligand-receptor recognition, sterol-sensing domain, transmembrane proteins
- MeSH terms
- Patched-1 Receptor, Protein Domains, Binding Sites, Cholesterol, Fatty Acids, Humans, Ligands, Models, Molecular, Palmitic Acid, Cryoelectron Microscopy, Hedgehog Proteins, Lipoylation
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