Mechanisms of metal transport and substrate specificity of the ZIP metal transporters

Metal transporters are critically involved in metal homeostasis in living organisms. The Zrt-/Irt-like protein (ZIP) family consists of divalent metal transporters ubiquitously present in all kingdoms of life. By governing influx of zinc, iron, manganese, and other life-essential or life-threatening transition metals, the ZIPs participate in numerous physiological and pathological processes and represent potential drug targets against human diseases, including cancers. My laboratory has been working on structural biochemistry of the ZIP family in the last decade. In this talk, I will be presenting our recent studies on two interrelated topics – transport mechanism and substrate specificity. Structural, computational, modeling, and biochemical evidence will be presented to show that a prototypic bacterial ZIP utilizes an elevator-type transport mode to achieve alternating access. The substrate specificity study on a human ZIP will highlight the discovery of a hidden selective filter which is a key determinant of substrate preference. We believe this work will promote mechanistic study and rational engineering of the ZIPs for applications.