The bioinorganic chemistry of zinc finger proteins: from H2S reactivity to regulatory function

The National Institute of General Medical Sciences awarded the University of Maryland, Baltimore $427,625 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to fund research on the bioinorganic chemistry of zinc finger proteins and hydrogen sulfide reactivity.

The research investigates how hydrogen sulfide, a gaseous signaling molecule, modifies cysteine residues in zinc finger proteins through persulfidation, converting thiols to persulfides and potentially disrupting their ability to bind nucleic acids and regulate gene expression. Because zinc finger proteins comprise approximately 8 percent of all eukaryotic proteins, the study addresses a largely unexplored mode of cellular regulation. The research program employs a molecules-to-proteomics approach, combining rigorous biochemical and bioanalytical studies to identify specific persulfidation sites and their formation mechanisms, alongside cell-based functional assays using reporter systems and persulfide-specific proteomics to characterize which zinc finger protein classes undergo persulfidation and how this modification modulates gene expression.

Work is performed in Baltimore, Maryland. The period of performance runs from July 1, 2026, through March 31, 2031. The award is classified as a Project Grant, the assistance type used by the National Institute of General Medical Sciences for investigator-initiated basic research supporting single or multiple research projects within a specified period.

Abstract

Zinc finger (ZF) proteins are the most abundant class of zinc-coordinated proteins in eukaryotes, playing essential roles in regulating gene expression. These proteins utilize structural domains with conserved cysteine and histidine residues that coordinate a zinc ION forming compact, stable structures to enable precise binding to DNA or RNA. This structural paradigm has long served as the foundation for understanding ZF protein function. Our laboratory has discovered an intriguing new paradigm for ZF protein reactivity that involves the gaseous signaling molecule, hydrogen sulfide (H2S). H2S is a gasotransmitter that modifies cysteine residues through persulfidation, converting thiols (RSH) to persulfides (rssh). We have obtained exciting data demonstrating that this modification can dramatically alter protein function by disrupting the ability of ZF domains to bind nucleic acids, potentially reshaping their regulatory roles in gene expression. Given that ZF proteins comprise approximately 8% of all eukaryotic proteins, this discovery reveals a significant and largely unexplored mode of cellular regulation. Our research program seeks to define the biochemical and cellular mechanisms by which H2S signals through ZF protein persulfidation. We plan to address the following key questions: (1) which types of ZFS are persulfidated? (2) how does ZF persulfidation modulate gene expression? And (3) what are the molecular triggers that turn on H2S signaling? We will employ a 'molecules-to-proteomics' approach, utilizing rigorous biochemical and bioanalytical studies to identify specific persulfidation sites and their mechanisms of formation. In parallel, cell-based studies, including reporter assays, will assess the functional impact of ZF persulfidation on gene expression. Persulfide specific proteomics will be used to identify classes of ZF proteins that undergo persulfidation and to elucidate the molecular cues that regulate this process. Our research program aims to determine how H2S reprograms ZF protein function. This work will offer new insights into how this ancient signaling molecule influences gene regulation.