Transport, substrate specificity and regulation mechanisms of the ZIP transition metal transporters

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Transport, substrate specificity and regulation mechanisms of the ZIP transition metal transporters Abstract Some d-block transition metals (Fe, Zn, Mn, Cu, Co, Mo and Ni) play key roles in catalysis, structural stability of macromolecules, gene expression regulation and cell signaling. Living organisms have evolved systemic and cellular mechanisms to harness the unique chemical properties of beneficial trace elements and meanwhile to avoid toxicity upon overdose or mislocalization. The long-term goal of this research program is to clarify structural and molecular basis of transition metal biology with a current focus on zinc, the second most abundant trace element after iron in human body. Intracellular zinc concentration and subcellular distribution are tightly regulated by coordinated action of zinc buffers/mufflers, zinc storage proteins, zinc-utilizing macromolecules, zinc- responsive transcription factors and two specific zinc transporter families – the zinc transporter (ZnT, SLC30A) family and the Zrt-/Irt-like protein (ZIP, SLC39A) family. In this MIRA application, our research focuses on the ZIP family which is not only a central player in zinc homeostasis and zinc signaling but also critically involved in Fe and Mn metabolism in humans. As an ancient protein family, the ZIPs are almost ubiquitous in living organisms and play fundamental roles in transitional metal acquisition from environment and distribution/redistribution within the body. In humans, a total of fourteen ZIPs exert distinct biological functions and are associated with a variety of diseases, including several types of cancer. Albeit important biological functions and critical roles in human health, much less is known about the ZIPs when compared to that of the ZnT family. The last several years have witnessed rapid progress in research of the ZIPs made by metal biology community including this research program. In the next five years we are planning to tackle the following three important questions to further the understanding of the ZIPs at molecular level: (1) What is the structural basis of substrate transport through the transporter? (2) Given the distinct substrate preference among the family members, what are the key factors determining substrate specificity? Can substrate preference be fine-tuned through adjusting the identified key factors for potential applications in agriculture and environmental protection? and (3) What is the molecular basis of zinc-regulated post-translational regulation of human ZIPs? Through a combination of structural, biochemical, biophysical and cell biological approaches, we are going to work on representative family members, including a prokaryotic ZIP, the structure of which has provided a structural framework for the entire family, a couple of human ZIPs associated with diseases and undergoing zinc- dependent post-translational regulation, and a plant ZIP critically involved in cadmium uptake from soil and accordingly a potential target for protein engineering. Success of this project will improve the understanding of transport, substrate specificity and regulation of the ZIP transporters, and also shed light on mechanistic studies of many other membrane transporters, particularly those involved in transition metal homeostasis and signaling.