Hedgehog patterning activity: Role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain
Open accessAbstract
Autocatalytic processing mediated by the carboxyterminal domain of the hedgehog (hh) protein precursor (Hh) generates an amino-terminal product that accounts for all known signaling activity. The role of autoprocessing biogenesis of the hh signal has been unclear, since a truncated unprocessed protein lacking all carboxy-terminal domain sequences retains signaling activity. Here, we present evidence that the autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signaling domain and influences its spatial and subcellular distribution. We demonstrate that truncated unprocessed amino-terminal protein causes embryonic mispatterning, even when expression is localized to cells that normally express Hh, thus suggesting a role for autoprocessing in spatial regulation of hh signaling. This type of processing also appears to operate in the biogenesis of other novel secreted proteins.
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Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations in SLOS.
“Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations. Activity of this signaling factor and its distribution are regulated by posttranslational attachment of cholesterol to its amino terminus [26,27,28].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [26]
The Abstract and Discussion report that a lipophilic modification influences Hedgehog signaling activity and distribution. But the paper does not identify the modifying group as cholesterol; its discussion of “The Nature of the Modification” places the linkage at the carboxyl terminus of the amino-terminal signaling domain, not at its amino terminus. The citation is attached to the modification sentence, not the preceding sentence about low cholesterol and malformations. (LLM, conf=0.88)
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Research works printed but not linked: 3
- [2]2. Ausubel, F.M ∙ Brent, R ∙ Kingston, R.E ... (Editors) Current Protocols in Molecular Biology Greene Publishing Associates and Wiley-Interscience, New York, 1995 Google Scholar
- [3]3. Blackledge, J.A ∙ Alexander, J.A Polyethylene membrane as a sample support for direct matrix-assisted laser desorption/ionization mass spectrometric analysis of high mass proteins Anal. Chem. 1995; 67:843-848 Crossref Scopus (127) PubMed Google Scholar
- [4]4. Bordier, C Phase separation of integral membrane proteins in Triton X-114 solution J. Biol. Chem. 1981; 256:1604-1607
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- Authors
- Porter, J. A., Ekker, S. C., Park, W.-J., von Kessler, D. P., Young, K. E., Chen, C.-H., Ma, Y., Woods, A. S., Cotter, R. J., Koonin, E. V., & Beachy, P. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Corresponding author
- Koonin, Eugene V
- Beachy, Philip A
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1996-07
- Volume
- 86
- Issue
- 1
- Pages
- 21-34
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1964361564
- Cited by
- 533
- References
- 0
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 16 · 2022: 10 · 2021: 16 · 2020: 10 · 2019: 17 · 2018: 22 · 2017: 10 · 2016: 17 · 2015: 9 · 2014: 12 · 2013: 13 · 2012: 18
- FWCI
- 11.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- 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 › Developmental Biology and Gene Regulation
- Keywords
- Hedgehog signaling, autoprocessing, C-terminal domain, thioester intermediate, covalent modification, embryonic patterning, spatial regulation of signaling, secreted proteins, protein processing
- MeSH terms
- Animals, Cells, Cultured, Drosophila, Esters, Lipids, Molecular Sequence Data, Proteins, Mass Spectrometry, Sulfhydryl Compounds, Water, Signal Transduction, Consensus Sequence, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Drosophila Proteins, Hedgehog Proteins
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