Mechanisms of metal receptors controlling inorganic phenotypes

The National Institute of General Medical Sciences awarded Michigan State University (doing business as Henry Ford Health+Michigan State University Health Sciences) $471,000 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support research on mechanisms of metal receptors controlling inorganic phenotypes.

The funded research characterizes metalloregulatory proteins that control genes and cell cycle regulatory proteins in response to metal ions, with three primary objectives: determining how zinc regulons are controlled through protein-RNA interactions; establishing mechanisms by which copper, zinc, and mercury sensing switches control DNA topology within RNA polymerase promoter complexes and applying these insights to develop new metal ion sensors; and developing quantitative metallomic methods to measure how inorganic phenotypes vary across cells involved in commensal or pathophysiological interactions with the human host.

Work is performed in East Lansing, Michigan. The period of performance runs through April 30, 2031. This is a Project Grant, the standard assistance type for investigator-initiated research under NIGMS's mission to support basic research that advances understanding of biological processes and lays the foundation for disease diagnosis, treatment, and prevention.

Abstract

There is a growing need in the biomedical research community to understand the fundamental roles and mechanisms that regulate inorganic chemistry involved in cellular physiology. While many of the d-block metals have been labeled as 'trace elements,' from a cellular point of view this is a misnomer: the intracellular concentrations of zinc and iron are routinely maintained at much higher levels (i.e., 0.6 MM). These insights, as well as the emerging literature linking metal physiology to many human disease states, underscore the importance of establishing the fundamental principles, general pathways, and macromolecular mechanisms employed to manage the large numbers of metal ions required for optimal health of a cell. The PI's lab has developed innovations to enable the discovery of novel pathways and principles. This involves mechanistic and structural characterization of metal receptors that switch on and off genes or the activity of cell cycle regulatory proteins in a metal dependent manner. One function of these metalloregulatory proteins is to control the activity of cellular machinery that maintains metal concentrations within narrow ranges. The goals of this proposal are to: a) determine how zinc regulons are controlled by metalloregulatory switching events through newly discovered protein-RNA interactions; b) establish mechanisms for how copper, zinc, and mercury sensing metalloregulatory switches control the topology of DNA within an RNA polymerase promoter complex, and then applying these insights to the development of new types of metal ION sensors; and c) develop quantitative metallomic methods that enable researchers across the biomedical research continuum to address the question of how quantitative inorganic phenotypes vary across cells involved in commensal or pathophysiological interactions with the human host. A second goal of the proposed study tests the hypothesis that regulatory zinc fluxes exert instructive control over the mammalian cell cycle through specific, receptor-mediated processes. Zinc has traditionally been viewed as a static cofactor involved in protein structure and enzyme catalysis. Recent studies support the idea that zinc binding sites in regulatory proteins respond to transient fluctuations in zinc availability and are switched on and off in ways that directly regulate key cellular events. A major objective of this proposal is to use biochemical, protein biochemistry and spectroscopic approaches to understand how the influx and efflux of zinc regulate the cell cycle. New chemical tools will be deployed to probe and control the concentration of zinc to further our understanding of zinc signaling pathways. In addition, we will leverage emerging techniques in x-RAY absorption and emission spectroscopy and mass spectrometry to understand the chemical environment of the metal in the zinc-binding proteins that regulate cell cycle progression. The results from these studies will describe a mechanism of zinc signaling during the meiotic cell cycle. As a whole, these studies address the gaps in our understanding of the inorganic chemistry of cellular physiology.