Unraveling novel roles for iron-sulfur cluster trafficking proteins in Fe-S cluster and cell envelope biogenesis

University Of South Carolina At Columbia, Columbia SC

Investigators

Abstract

The goal of this project is to understand how organisms integrate the essential metal iron with core metabolic pathways at the cellular level. Despite the cellular requirement for iron, it is still not fully understood how essential iron-dependent metabolic pathways respond to changes in iron availability. Knowledge gained from this project will provide insight into the critical role of iron in organisms ranging from bacteria to humans by revealing how cellular iron balance and cell metabolism are coordinated. This project will also support the participation of students in STEM fields by providing research experiences for undergraduates who attend Benedict College. The students will conduct summer research on the project aims in the lab of the primary investigator at the University of South Carolina, with continued mentoring during the academic year(s) after completion of the summer research through finishing college. The additional mentoring interactions will maintain student engagement and allow for evaluation of the research and mentoring program’s impact on student interest in STEM research and career paths. Iron is required by nearly all forms of life due to its role as a cofactor in critical pathways, including respiration, the Krebs cycle, DNA synthesis and repair, and gene regulation. Iron-sulfur (Fe-S) clusters are the iron cofactors utilized by proteins in these cellular pathways. This research focuses on revealing the molecular details of how Fe-S clusters are formed and trafficked to the appropriate Fe-S cluster protein within the cell (Fe-S cluster biogenesis), even under stress conditions that perturb iron homeostasis. In the model organism, Escherichia coli, our multidisciplinary team will combine microbial genetics, analytical chemistry, protein biochemistry, and quantitative mass spectrometry-based proteomic approaches to determine the role of monothiol glutaredoxins and their binding partner proteins in Fe-S cluster trafficking. Based on preliminary data, our hypothesis is that monothiol glutaredoxins form a storage pool of Fe-S clusters that is conditionally required for reloading Fe-S cluster trafficking or other target proteins under stress. Furthermore, through its interaction with partner proteins, these glutaredoxins may coordinate Fe-S cluster metabolism with cell envelope biogenesis in E. coli. Our interdisciplinary studies will provide a detailed molecular understanding of monothiol glutaredoxin function providing insight into the cellular mechanisms for crosstalk between Fe-S cluster biogenesis and cell envelope biogenesis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.