# Structures and Mechanisms of Iron-Sulfur Proteins in Redox Control and Stress Response

> **NIH NIH R35** · UNIVERSITY OF NEBRASKA LINCOLN · 2020 · $371,250

## Abstract

PROJECT SUMMARY
Iron-sulfur (Fe-S) clusters are ancient cofactors composed of multiple iron and sulfur atoms. They are
fundamental to numerous biological processes in all domains of life. Owing to the rich, tunable redox reactivity
and selectivity of the cluster, Fe-S proteins play multifaced roles in redox control under both physiological and
stress conditions. The roles of Fe-S proteins in redox control are vital for the maintenance of normal cellular
functions and cell survival, and thus they are tightly linked to health and disease such as cancer and diabetes in
human and bacterial infection. This contrasts vividly with the lack of functional, structural and mechanistic
understanding of many Fe-S proteins in the cellular control of redox homeostasis, particularly in the three core
aspects that are addressed in this MIRA proposal: i) redox sensing and transcriptional regulation by Fe-S proteins;
ii) assembly, transfer and repair of Fe-S clusters; and iii) crosstalk between Fe-S proteins and the low-molecular-
weight (LMW) thiols in redox hemostasis. Several Fe-S proteins-mediated mechanisms for redox control in
mycobacteria will be used as examples to elaborate our research goals and approaches in this proposal,
including i) redox sensing and transcriptional regulation by a unique family of Fe-S cluster-bound transcription
factors in the WhiB-like family; ii) assembly, transfer and repair of Fe-S clusters by the SUF system; and iii)
mycothiol in Fe-S cluster homeostasis. The proposed research program is built on the unique combination of
skills and rich research experience in my research team that are crucial for characterizing the oxygen-sensitive
metal-binding proteins. We recently determined the first and long-desired Fe-S cluster-bound structure of the
monomeric transcription factor WhilB1 from Mycobacterium tuberculosis and established a new mechanism of
bacterial transcriptional regulation mediated by this protein. By combining structural, spectroscopic and
biochemical approaches in vitro with molecular biology in vivo, we are poised to determine: i) the structural basis
of redox reactivity and ligand selectivity in Fe-S clusters; ii) the mechanism by which the redox state and integrity
of the Fe-S cluster allows these proteins to sense redox state and regulate transcription; iii) the structural
biochemistry of Fe-S cluster biosynthesis and regulation; and iv) the role of non-proteinaceous thiols in
modulating Fe-S cluster-mediated redox control. Altogether, the proposed research program will establish a new
line of ground-breaking research in an understudied aspect of redox homeostasis. The strategies developed
from the proposed program will be instrumental for studies on the newly discovered Fe-S cluster system, such
as those in the DNA repair and RNA metabolism in response to oxidative stress. Because of their critical roles
in redox control, the study of the novel mechanisms of these Fe-S proteins will not only shed light on the
fund...

## Key facts

- **NIH application ID:** 10029204
- **Project number:** 1R35GM138157-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA LINCOLN
- **Principal Investigator:** Limei Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029204

## Citation

> US National Institutes of Health, RePORTER application 10029204, Structures and Mechanisms of Iron-Sulfur Proteins in Redox Control and Stress Response (1R35GM138157-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10029204. Licensed CC0.

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