Regulation of Cell Signaling by Transition Metal Dynamics

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DESCRIPTION (provided by applicant): Transition metals are critical to all forms of life, and metal ions play vital roles in a diverse array of fundamental biological processes. Metal dyshomeostasis is a central feature of a broad spectrum of human diseases, yet elucidating whether altered metal status is a cause or consequence of disease is exceedingly difficult without a basic understanding of how metals influence normal cellular functions. While there are some well-known examples of how metals can drive cellular change, there are major gaps in our understanding of how changes in metal status influence cell physiology. This gap is particularly notable for zinc. There is growing evidence that zinc changes in response to cell state, and may function in signal transduction and biological regulation. For example, massive accumulation of zinc is required for meiotic maturation of oocytes and fertilization leads to zinc sparks; stimulation of bone marrow derived mast cells leads to zinc waves. Furthermore, my lab has shown that calcium signaling events in neurons and epithelial cells lead to mobilization of zinc, raising the intriguing possibility that zinc functions as a novel second messenger. But in al of these cases, the downstream effectors, i.e. the proteins that sense changes in zinc in order to regulate cellular processes remain a complete mystery. The core hypothesis of this project is that the regulation of cellular zinc dictates occupancy of the zinc proteome, providing a novel link between dynamic metal regulation and a wide swath of cellular signaling responses. The implication of this hypothesis is that changes in zinc status - either dynamically during physiological signaling, or permanently as a consequence of disease - fine-tune the activity of hundreds, if not thousands of zinc-dependent proteins, establishing zinc as a master regulator of cellular function. Current dogma in zinc biology asserts that the ~ 2000 proteins that comprise the zinc proteome bind zinc cons