Author

Enis Sanchez

Date of Award

Fall 2021

Document Type

Open Access Thesis

Department

Chemistry and Biochemistry

First Advisor

F. Wayne Outten

Abstract

Biogenesis of iron-sulfur (Fe-S) clusters is an essential process in living organisms due to the critical role of Fe-S cluster proteins in a myriad of cellular functions. During the assembly of Fe-S clusters, multi-protein complexes are used to drive the mobilization and protection of reactive sulfur and iron intermediates, regulate assembly of various Fe-S clusters on an ATPase-dependent, multi-protein scaffold, and target nascent clusters to their downstream protein targets. In each of the Fe-S cluster biogenesis steps, specific protein-protein interactions (PPIs) are required for proper function of the assembly pathway. The target pathway is the sulfur formation (Suf) pathway for Fe-S cluster assembly found in bacteria and archaea. In Escherichia coli, the Suf pathway functions as an emergency pathway under conditions of iron limitation or oxidative stress. In other pathogenic bacteria, such as Mycobacterium tuberculosis and Enterococcus faecalis, the Suf pathway is the sole source for Fe-S clusters. The goal of this research is to characterize PPIs critical for bacterial Fe-S cluster assembly, which could act as a potential target for the development of novel antibacterial compounds to disrupt those interactions. Important PPIs between the Suf pathway and additional upstream and downstream cluster carrier proteins provide biologically relevant targeting functions and the ability for “crosstalk” between cluster assembly pathways. Genetic and biochemical studies suggest that in vivo Fe-S cluster trafficking utilizes complex mechanisms. Herein, we characterize cluster trafficking interactions between SufA and the upstream Fe-S cluster trafficking protein, Grx4. The percentage and rate of cluster transfer suggests that Grx4 may transfer its cluster to SufA in vivo, as a unidirectional proceMycobacterium tuberculosisss.

Available for download on Friday, December 15, 2023

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