Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched
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Abstract
Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity of the 7-transmembrane protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of the Patched protein reveals striking transmembrane domain similarities to prokaryotic RND transporters. A central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting Patched activity in cholesterol transport. Cholesterol activity in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability.
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GPR175 is enriched in cilia in the presence of SHH and might regulate maximal activation of pathways downstream of SMO by coupling to Gαi, leading to decreased cAMP levels and inhibiting PKA-mediated formation of GLI3R.
“Furthermore, the 7-transmembrane receptor GPR175 (also known as TPRA1 or TPRA40) is enriched in cilia in the presence of SHH, and might regulate maximal activation of pathways downstream of SMO by coupling to the inhibitory Gα protein, Gαi, leading to decreased cAMP levels and inhibiting PKA-mediated formation of GLI3R 116.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [116]
The Abstract and ‘Redistribution of membrane cholesterol by PTCH1’ section discuss SHH, PTCH1, and SMO regulation, but do not address GPR175. Searches for GPR175/TPRA1/TPRA40 and Gαi/cAMP/PKA/GLI3R found no passage supporting the claimed ciliary enrichment or signaling mechanism. (LLM, conf=0.76)
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Research works printed but not linked: 3
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Cellular signalling by primary cilia in development, organ function and disease
Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B., & Christensen, S. T. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0116-9 · Cited by 845 · see citing works
- Authors
- Zhang, Y., Bulkley, D. P., Xin, Y., Roberts, K. J., Asarnow, D. E., Sharma, A., Myers, B. R., Cho, W., Cheng, Y., & Beachy, P. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- University of Illinois Chicago (US)
- Stanford Medicine (US)
- Corresponding author
- Cho, Wonhwa
- Cheng, Yifan
- Beachy, Philip A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 175
- Issue
- 5
- Pages
- 1352-1364.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6326742
- OpenAlex
- W2809141540
- Cited by
- 239
- References
- 72
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 21 · 2023: 35 · 2022: 33 · 2021: 47 · 2020: 40 · 2019: 38 · 2018: 2
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (R01-GM129325, P41-GM103311, R01GM102498, R01GM098672, S10OD020054, S10OD021741, R35GM122530)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- Patched, Hedgehog signaling, Smoothened, cholesterol transport, RND transporters, PTCH1, basal cell carcinoma, transmembrane domain structure
- MeSH terms
- Patched-1 Receptor, Amino Acid Sequence, Animals, Cell Line, Cholesterol, Escherichia coli, Humans, Recombinant Proteins, Signal Transduction, Sequence Alignment, Protein Structure, Tertiary, Evolution, Molecular, Dimerization, Cryoelectron Microscopy, Multidrug Resistance-Associated Proteins, ATP-Binding Cassette, Sub-Family C Proteins, Escherichia coli Proteins, Mice, Hedgehog Proteins, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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