Chemoselective Proteomics, Zinc Fingers, and a Zinc(II) Model for H₂S Mediated Persulfidation

Abstract

The gasotransmitter hydrogen sulfide (H2S) is thought to be involved in the post‐translational modification of cysteine residues to produce reactive persulfides. A persulfide‐specific chemoselective proteomics approach with mammalian cells has identified a broad range of zinc finger (ZF) proteins as targets of persulfidation. Parallel studies with isolated ZFs show that persulfidation is mediated by ZnII, O2, and H2S, with intermediates involving oxygen‐ and sulfur‐based radicals detected by mass spectrometry and optical spectroscopies. A small molecule ZnII complex exhibits analogous reactivity with H2S and O2, giving a persulfidated product. These data show that ZnII is not just a biological structural element, but also plays a critical role in mediating H2S‐dependent persulfidation. ZF persulfidation appears to be a general post‐translational modification and a possible conduit for H2S signaling. This work has implications for our understanding of H2S‐mediated signaling and the regulation of ZFs in cellular physiology and development.