4.8 Article

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

Journal

NATURE CHEMICAL BIOLOGY
Volume 17, Issue 12, Pages 1271-1280

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00907-2

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Oxysterols, hydroxylated cholesterol metabolites, have important roles in health and disease. The chemoproteomics probe for 20(S)-hydroxycholesterol identified specific interactions with proteins involved in immune response and cancer. 20(S)-OHC was found to be a highly selective ligand for the protein transmembrane protein 97, providing insights into its biological activity and potential therapeutic targets.
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 sigma 2 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. A chemoproteomics profile of the human metabolite 20(S)-hydroxycholesterol exposes its broad connections to the immune system and cancer, revealing it to be a highly selective ligand for the orphan receptor Tmem97 (the sigma 2 receptor).

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