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

ZIP过渡金属转运蛋白的转运、底物特异性和调控机制

基本信息

批准号：
10616707
负责人：
Jian Hu
金额：
$ 39万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

项目摘要

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.

ZIP过渡金属转运蛋白的转运、底物特异性和调控机制抽象的一些 d 区过渡金属（Fe、Zn、Mn、Cu、Co、Mo 和 Ni）在催化、结构稳定性方面发挥着关键作用大分子、基因表达调控和细胞信号传导已经系统性地进化。细胞机制利用有益微量元素的独特化学性质，同时避免过量或错误定位时的毒性该研究计划的长期目标是阐明结构。和过渡金属生物学的分子基础，目前重点关注第二丰富的微量元素锌人体内仅次于铁的元素，细胞内锌浓度和亚细胞分布受到严格调节。通过锌缓冲剂/消声器、锌储存蛋白、锌利用大分子、锌-的协调作用响应转录因子和两个特定的锌转运蛋白家族 - 锌转运蛋白（ZnT、SLC30A）家族和 Zrt-/Irt 样蛋白 (ZIP、SLC39A) 家族在此 MIRA 应用中，我们的研究重点是 ZIP 家族不仅是锌稳态和锌信号传导的核心参与者，而且还关键参与人类的铁和锰代谢作为一个古老的蛋白质家族，ZIPs在生物体中几乎无处不在。有机体在从环境和环境中获取过渡金属方面发挥着重要作用在人体中，共有 14 个 ZIP 发挥着不同的生物学功能。并且与多种疾病有关，包括几种类型的癌症。与 ZIP 相比，人们对 ZIP 的功能和关键作用知之甚少。 ZnT家族近几年来金属生物学ZIPs的研究取得了快速进展。包括此研究计划在内的社区在未来五年内计划解决以下三个问题在分子水平上进一步理解 ZIP 的重要问题：（1）结构基础是什么 (2) 考虑到家族中不同的底物偏好各位成员，决定底物特异性的关键因素是什么？可以微调底物偏好吗？通过调整已确定的农业和环境保护潜在应用的关键因素？ (3) 人类 ZIP 的锌调节翻译后调节的分子基础是什么？结合结构、生物化学、生物物理和细胞生物学方法，我们将致力于代表性的家族成员，包括原核ZIP，其结构提供了结构整个家庭的框架，几个与疾病和接受锌相关的人类 ZIP 依赖的翻译后调节，以及植物 ZIP 与土壤和土壤中镉的吸收密切相关该项目的成功将加深人们对 ZIP 转运蛋白的转运、底物特异性和调节，并为机制研究提供了线索许多其他膜转运蛋白，特别是那些涉及过渡金属稳态和信号传导的膜转运蛋白。