# The Role of Zinc Fingers in H2S Signaling

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $369,442

## Abstract

This proposal focuses on understanding the role of zinc finger (ZF) proteins in H2S signaling. ZFs are highly
abundant proteins that play critical roles in transcriptional and translational regulation. ZFs are cysteine rich and
use zinc as a cofactor. The role of zinc in ZFs has long been considered to be solely structural; however, evidence
for a new paradigm is emerging in which the zinc ion plays a more reactive role. This evidence includes the
finding that hydrogen sulfide (H2S) targets ZF proteins. H2S is an endogenous gasotransmitter that has gained
attention in recent years as a biological signaling molecule via cysteine persulfidation. This process is now
proposed as a type of protein post-translational modification that plays a critical role in cell signaling. It has been
shown that H2S signaling is associated with inflammation, neuromodulation, transcription and metabolism, with
aberrant H2S activity linked to cardiovascular, neurological, inflammatory and metabolic diseases. Despite the
growing appreciation for the importance of H2S in biology, our understanding of the biological roles of H2S is
limited. The macromolecular targets of H2S are not clearly defined, and the mechanism of H2S action has not
been determined in most cases. We have obtained exciting proteomics data that identifies numerous ZFs as
cellular targets for H2S. We have also reported that a specific ZF, tristetraprolin (TTP), reacts with H2S in a zinc
and O2 dependent manner to give persulfidated cysteine intermediates and modulate TTP structure. These
structural changes transmit the `signal' from H2S by abrogating the RNA binding ability of TTP. In this proposal
we aim to (i) identify the ZFs that are targeted by H2S in cells using a persulfide selective proteomics strategy (ii)
determine the reactivity and mechanism of H2S with ZFs by applying a suite of biochemical and biophysical
methods (including cryo-ESI-mass spectrometry, fluorescence quenching, EPR, XAS and NMR spectroscopies,
and fluorescence anisotropy binding assays) to ZF proteins, ZF peptides and synthetic model complexes and
(iii) determine how zinc speciation impacts H2S targeting of ZFs by using a combined LC-ICP-MS, proteomics
and antibody/microarray strategy. This `molecules to proteomics' approach will allow us to understand the largely
unexplored role of ZF proteins in H2S signaling, and has the potential to transform our understanding of H2S
signaling.

## Key facts

- **NIH application ID:** 10096833
- **Project number:** 1R01GM139854-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** SARAH L MICHEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,442
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10096833

## Citation

> US National Institutes of Health, RePORTER application 10096833, The Role of Zinc Fingers in H2S Signaling (1R01GM139854-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10096833. Licensed CC0.

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