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.
