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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10616707
• 关键词: Agriculture; Biochemical; Biological; Biological Process; Biology; Biophysics; Buffers; Cadmium; Catalysis; Cells; Communities; Disease; Environment; Environmental Protection; Family; Family member; Five-Year Plans; Gene Expression Regulation; Goals; Health; Health protection; Homeostasis; Human; Human Genome; Human body; Iron; Malignant Neoplasms; Membrane Transport Proteins; Metabolism; Metals; Molecular; Organism; Overdose; Physiological Processes; Plants; Play; Post-Translational Regulation; Protein Engineering; Protein Family; Proteins; Regulation; Research; Role; Signal Transduction; Soil; Structure; Substrate Specificity; Toxic effect; Trace Elements; Transition Elements; Work; Zinc; cancer type; chemical property; improved; macromolecule; preference; programs; success; transcription factor; uptake; zinc-binding protein

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、底物特异性及其调控机制 摘要 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关键作用 大分子、基因表达调控和细胞信号传导。生物体已经进化出系统性的， 利用有益微量元素的独特化学性质的细胞机制， 避免过量或错误定位时的毒性。这项研究计划的长期目标是阐明结构性 和过渡金属生物学的分子基础，目前的重点是锌， 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控 通过锌缓冲剂/消音剂、锌储存蛋白、锌利用大分子、锌- 响应性转录因子和两个特定的锌转运蛋白家族--锌转运蛋白（ZnT、SLC 30 A） 家族和Zrt-/Irt样蛋白（ZIP，SLC 39 A）家族。在这个MIRA应用程序中，我们的研究重点是 ZIP家族不仅是锌稳态和锌信号传导的中心参与者，而且还关键地参与了 人体的铁和锰代谢。作为一个古老的蛋白质家族，拉链在生活中几乎无处不在 在环境中获取过渡金属的过程中起着重要作用， 身体内的分布/再分布。在人类中，总共有14个拉链发挥不同的生物功能 并且与多种疾病有关，包括几种类型的癌症。尽管重要的生物学 在人类健康中的功能和关键作用，与人类健康相比， ZNT家族近几年来，金属生物学制备的ZIPs的研究进展迅速 包括这项研究计划。在未来五年，我们计划解决以下三个问题 在分子水平上进一步理解ZIPs的重要问题是：（1）结构基础是什么 基质通过运输机运输的过程吗(2)鉴于不同的基板偏好之间的家庭 各位委员，决定底物专一性的主要因素是什么？基质偏好可以微调吗 通过调整确定的农业和环境保护潜在应用的关键因素？ 锌调控人类ZIPs翻译后调控的分子基础是什么？通过 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，其结构提供了结构上的优势。 整个家庭的框架，一对夫妇的人类拉链与疾病和经历锌- 依赖的翻译后调节，和植物ZIP关键参与从土壤中吸收镉， 因此是蛋白质工程的潜在靶标。该项目的成功将提高对 运输，底物特异性和ZIP转运蛋白的调节，也阐明了机制研究 许多其他膜转运蛋白，特别是那些参与过渡金属稳态和信号传导的转运蛋白。

项目成果

Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter.

• DOI: 10.1038/s41467-023-36048-4
• 发表时间: 2023-01-24
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Zhang, Yao;Jiang, Yuhan;Gao, Kaifu;Sui, Dexin;Yu, Peixuan;Su, Min;Wei, Guo-Wei;Hu, Jian
• 通讯作者: Hu, Jian

Cluster learning-assisted directed evolution.

• DOI: 10.1038/s43588-021-00168-y
• 发表时间: 2021-12
• 期刊: NATURE COMPUTATIONAL SCIENCE
• 作者: Qiu, Yuchi;Hu, Jian;Wei, Guo-Wei
• 通讯作者: Wei, Guo-Wei

Cell-based transport assay to study kinetics and substrate specificity of human ZIPs.

基于细胞的转运测定，用于研究人类 ZIP 的动力学和底物特异性。

• DOI: 10.1016/bs.mie.2023.05.013
• 发表时间: 2023
• 期刊: Methods in enzymology
• 作者: Jiang,Yuhan;Sui,Dexin;Hu,Jian
• 通讯作者: Hu,Jian