Transition metal homeostasis is a key process for all forms of life. Metal homeostasis can be disrupted by a variety of environmental or genetic factors. For example, oxygen can alter the oxidation state of some transition metals, such as iron and copper, thereby altering their bioavailability and toxicity. In addition, the requirement for multiple transition metals for correct cell function can be problematic if some transition metals compete with each other for binding to similar protein active sites. For example, under anaerobic conditions in bacteria, iron is combined with nickel in the active sites of the Ni-Fe hydrogenase family of enzymes. During anaerobic growth bacteria increase nickel uptake to provide for hydrogenase maturation. However, excess nickel is toxic to cells in part due to disruption of iron homeostasis. This project focuses on the transcription factor YqjI that regulates iron homeostasis genes in response to cellular nickel accumulation. YqjI is a nickel-dependent metalloregulatory protein that represses transcription of the ferric reductase YqjH under low nickel conditions. YqjI-dependent repression of yqjH is switched off when nickel levels rise above the concentration necessary for proper metalloprotein function leading to increased expression of yqjH. This project will characterize YqjI transcriptional regulation of the yqjH promoter and determine how nickel acts as an allosteric switch to control YqjI-dependent regulation. This project will also elucidate the in vivo function of the YqjH ferric reductase during iron homeostasis to understand why it is specifically cross-regulated by a nickel-responsive regulator (YqjI). Finally, this project will use genome-wide methods to identify new targets of YqjI transcriptional regulation in order to better understand how iron and nickel homoeostasis are integrated in E. coli.
This project will provide insight into the mechanisms of intracellular iron and nickel homeostasis and will contribute to the broader fields of bioinorganic chemistry and the study of environmental stress responses in biological systems. As part of th educational and outreach activities, minority undergraduate students from local Historically Black Colleges and Universities (HBCUs) in South Carolina will perform summer research projects directly related to these studies. In addition to learning biochemistry and molecular biology techniques, the students will participate in a year-long mentoring plan designed to increase minority involvement in scientific research and minority participation in Science, Technology, Engineering, and Mathematics (STEM) graduate programs.
