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MEMBRANE PROTEINS

There is a lock for every key

Nature Chemical Biology volume 17, pages 1214–1216 (2021)Cite this article

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Chemoproteomics-enabled identification of the targets of a hydroxylated cholesterol metabolite, 20(S)-hydroxycholesterol, reveals it to be the first reported endogenous ligand of the sigma-2 receptor, a drug target for neurodegeneration and neuropathic pain.

Unlike other lipids, cholesterol is not oxidized as an energy source. It is, however, frequently oxidized by enzymes or reactive oxygen species1. Such oxidation can occur at many positions on its complex hydrocarbon backbone, generating a large collection of oxysterols that have distinct structures and bioactivities. These metabolites can act as signaling molecules — with the different oxidation patterns constituting a molecular barcode — to affect diverse pathways including cholesterol homeostasis, nuclear hormone receptor signaling and membrane trafficking2,3. For example, 20(S)-hydroxycholesterol (20(S)-OHC) can engage the receptor Smoothened to activate Hedgehog signaling4. Yet, beyond this one target, the extent of the interactions of 20(S)-OHC with other proteins and signaling pathways has remained unknown. As they report in this issue of Nature Chemical Biology, Cheng et al. devised a tailored chemoproteomics strategy to map the binding partners of 20(S)-OHC and identified the sigma-2 receptor, encoded by TMEM97, as a selective binding target of this molecule5.

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Fig. 1: A chemoproteomics screen using a photocrosslinkable and clickable oxysterol probe revealed that 20(S)-OHC is an endogenous ligand of the σ2 receptor (TMEM97).

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Weizhi Yu & Jeremy M. Baskin

  2. Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA

    Weizhi Yu & Jeremy M. Baskin

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  1. Weizhi Yu
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  2. Jeremy M. Baskin
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Correspondence to Jeremy M. Baskin.

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Yu, W., Baskin, J.M. There is a lock for every key. Nat Chem Biol 17, 1214–1216 (2021). https://doi.org/10.1038/s41589-021-00908-1

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  • DOI: https://doi.org/10.1038/s41589-021-00908-1

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