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A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes

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Cheng, Yu-Shiuan, Zhang, Tianyi, Ma, Xiang, Pratuangtham, Sarida, Zhang, Grace C., Ondrus, Alexander A., Mafi, Amirhossein, Lomenick, Brett, Jones, Jeffrey J., Ondrus, Alison E.·2021·Nature Chemical Biology
DOI 10.1038/s41589-021-00907-2PMC PMC8607797

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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 their unique partitioning in membranes, the analysis of live-cell, proteome-wide interactions of OHCs remains an unmet challenge. Here, we present a structurally precise chemoproteomics probe for the biologically active molecule 20(S)-hydroxycholesterol (20(S)-OHC) and provide a map of its proteome-wide targets in the membranes of living cells. Our target catalog 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 transmembrane protein 97 (Tmem97/the σ2 receptor), enabling us to reconstruct the 20(S)-OHC-Tmem97 binding site. Our results demonstrate that multiplexed, quantitative analysis of cellular target engagement can expose new dimensions of metabolite activity and identify actionable targets for molecular therapy.

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Metadata

Authors
Cheng, Y.-S., Zhang, T., Ma, X., Pratuangtham, S., Zhang, G. C., Ondrus, A. A., Mafi, A., Lomenick, B., Jones, J. J., & Ondrus, A. E.
Affiliations
California Institute of Technology (US)
Corresponding author
  • Ondrus, Alexander A.
  • Ondrus, Alison E.
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2021-11-19
Volume
17
Issue
12
Pages
1271-1280
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/s41589-021-00907-2
PMC
PMC8607797
OpenAlex
W3133174712
Cited by
56
References
11
Citations by year
2026: 5 · 2025: 11 · 2024: 11 · 2023: 11 · 2022: 17 · 2021: 1
FWCI
3.14
Type
journal article
Language
en
Open access
Licence
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)
  • Margaret E. Early Research Trust
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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CoChat. (2026). Citation check: A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes. https://app.cochat.ai/papers/10.1038/s41589-021-00907-2
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Cheng, Y.-S., Zhang, T., Ma, X., Pratuangtham, S., Zhang, G. C., Ondrus, A. A., Mafi, A., Lomenick, B., Jones, J. J., & Ondrus, A. E. (2021). A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes. Nature Chemical Biology. https://doi.org/10.1038/s41589-021-00907-2