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A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes
Open accessPreprint — published as 10.1038/s41589-021-00907-2 · Paper page
Abstract
Oxysterols (OHCs) are hydroxylated cholesterol metabolites that play ubiquitous roles in health and disease. Due to the non-covalent nature of their interactions and unique partitioning in membranes, the analysis of live-cell, proteome-wide interactions of OHCs remains an unmet challenge. In this Resource, we present a structurally precise chemoproteomics probe for the osteogenic molecule 20(S)-hydroxycholesterol (20(S)-OHC) and provide a map of its proteome-wide targets in the membranes of living cells. Our target catalogue consolidates diverse OHC ontologies and demonstrates that OHC-interacting proteins cluster with specific processes in immune response and cancer. Competition experiments reveal that 20(S)-OHC is a chemo-, regio-, and stereoselective ligand for the protein Tmem97 (σ2 receptor), enabling molecular reconstruction of the Tmem97:20(S)-OHC binding site. Our results demonstrate that multiplexed, quantitative analysis of cellular target engagement can expose new dimensions of OHC activity and identify actionable targets for molecular therapy.
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Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566
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Metadata
- Authors
- Cheng, Y.-S., Zhang, T., Ma, X., Pratuangtham, S., Zhang, G., Ondrus, A., Mafi, A., Lomenick, B., Jones, J., & Ondrus, A.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Ondrus, Alexander
- Ondrus, Alison
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2021-02-22
- Volume
- 17
- Issue
- 12
- Pages
- 1271-1280
- ISSN
- 1552-4450 (ISSN-L)
- PMC
- PMC8607797
- OpenAlex
- W3133174712
- Cited by
- 56
- References
- 1
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 11 · 2022: 17 · 2021: 1
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health (GM07616)
- Gordon and Betty Moore Foundation (GBMF775)
- California Institute of Technology
- National Institutes of Health (1s10od010788-01a1, 1s10od020013-01)
- Beckman Institute, California Institute of Technology
- National Institute of General Medical Sciences (T32GM007616)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- oxysterols, chemoproteomics, TMEM97, sigma-2 receptor, protein-metabolite interactions, cell membrane binding, target engagement, ligand selectivity, immune response, cancer, cholesterol metabolites
- MeSH terms
- Animals, Cell Communication, Cell Membrane, Diazomethane, Humans, Hydroxycholesterols, Ligands, Pyridinium Compounds, 3T3 Cells, Streptavidin, Proteome, Mice, HEK293 Cells, Click Chemistry
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