Structure and Function of SWEET Sugar Transporters

SWEET糖转运蛋白的结构和功能

• 批准号: 10672222
• 负责人: Liang Feng
• 金额: $ 32.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672222
• 关键词: Affect; Amino Acids; Biological Process; Carbon; Communication; Complex; Coupled; Coupling; Cryoelectron Microscopy; Crystallography; Cystine; Cystinosis; Diabetes Mellitus; Dilated Cardiomyopathy; Disaccharides; Disease; Endoplasmic Reticulum; Family; Foundations; Goals; Homeostasis; Homologous Gene; Hormones; Human; Integral Membrane Protein; KDEL receptor; Knowledge; Light; Link; Lysosomal Storage Diseases; Lysosomes; Malignant Neoplasms; Mediating; Membrane; Membrane Proteins; Membrane Transport Proteins; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Molecular Conformation; Monosaccharides; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Physiological; Physiology; Play; Property; Protein Engineering; Protein Family; Protein Isoforms; Proteins; Protomer; Quality Control; Regulation; Research; Research Project Summaries; Resolution; Role; Solid; Spielmeyer-Vogt Disease; Structure; Targeted Research; Therapeutic; Transmembrane Transport; Work; blood glucose regulation; conformational conversion; disease-causing mutation; improved; insight; member; novel; pathogen; prototype; pyruvate carrier; receptor; sugar; triple helix

PROJECT SUMMARY Research over the past decade has uncovered the physiological importance and disease relevance of a large membrane transporter/receptor superfamily, called the MtN3 clan. For example, SWEET transporters are critical for sugar efflux and utilization; PQ-loop transporters have been linked to cystinosis and Batten disease; the mitochondrial pyruvate carrier controls a critical branch point of the central metabolic pathway and is implicated in cancer; and KDEL receptors are crucial for endoplasmic reticulum quality control and have been associated with dilated cardiomyopathy. Despite these diverse and important functions, we still know little about the molecular mechanisms of MtN3 transporters. Our overall objective is to provide structural and mechanistic insights that elucidate the physical basis of cross-membrane transport and shed light on the physiological functions and disease-causing malfunctions of MtN3 transporters. We will focus on SWEET sugar transporters, the founding members of the MtN3 family, and then expand our work to include related transporter families. In our prior research, we solved the first eukaryotic SWEET structure in an inward-open state and high-resolution structures of bacterial SemiSWEETS in multiple conformation states, shedding light on sugar transport by SWEETs and the alternating access mechanism more broadly. These results provide a solid foundation to further probe the mechanisms of MtN3 transporters. In this renewal application, we propose to extend this work to: (1) elucidate the structural basis of crosstalk and alternating access of eukaryotic SWEET; (2) dissect the substrate selectivity of SWEET transporters; and (3) determine the structural basis of the PQ-loop transporter. Understanding how MtN3 transporters work at the molecular level will provide rich insights into their transport mechanisms and crosstalk. Moreover, this work will provide a blueprint to understand the function of PQ-loop transporters and unravel the mechanisms underlying devasting lysosomal storage diseases. Ultimately, our work will produce essential knowledge that will facilitate targeting MtN3s for therapeutics. !

项目总结 在过去的十年中，研究已经发现了大量的 膜转运蛋白/受体超家族，称为MtN3家族。例如，甜味转运蛋白是至关重要的。 对于糖的外流和利用；PQ环转运体与胱氨酸病和巴滕病有关； 线粒体丙酮酸载体控制着中枢代谢途径的一个关键分支点，并与此有关 而KDEL受体对内质网质量控制至关重要，并与 患有扩张型心肌病。尽管有这些不同和重要的功能，但我们仍然对 MtN3转运蛋白的分子机制。我们的总体目标是提供结构性和机械性 阐明跨膜转运的物理基础并阐明生理上的 MtN3转运蛋白的功能和致病故障。我们将重点关注甜糖运输， MtN3家族的创始成员，然后将我们的工作扩大到包括相关的运输者家族。在……里面 我们之前的研究，我们解决了第一个真核生物甜味结构在向内开放的状态和高分辨率 具有多种构象的细菌半分子的结构，揭示了糖的转运 糖果和更广泛的交替访问机制。这些结果为进一步 探讨MtN3转运蛋白的作用机制。在此续期申请中，我们建议将这项工作扩展到：(1) 阐明真核甜蜜串扰和交替通达的结构基础；(2)底物的解剖 甜味转运体的选择性；以及(3)确定PQ环转运体的结构基础。 了解MtN3转运蛋白在分子水平上的工作原理将为我们提供对其转运蛋白的丰富见解 机制和串扰。此外，这项工作将为理解PQ环路的功能提供一个蓝图 转运蛋白和解开破坏性溶酶体储存疾病的潜在机制。最终，我们的工作 将产生基本的知识，将有助于将MtN3作为治疗的靶点。 好了！

项目成果

Structure of a eukaryotic SWEET transporter in a homotrimeric complex.

同源三聚体复合物中真核 SWEET 转运蛋白的结构

• DOI: 10.1038/nature15391
• 发表时间: 2015-11-12
• 期刊: Nature
• 影响因子: 64.8
• 作者: Tao Y;Cheung LS;Li S;Eom JS;Chen LQ;Xu Y;Perry K;Frommer WB;Feng L
• 通讯作者: Feng L

Structure and mechanism of human cystine exporter cystinosin.

人胱氨酸出口商cystinosin的结构和机制。

• DOI: 10.1016/j.cell.2022.08.020
• 发表时间: 2022-09-29
• 期刊: CELL
• 影响因子: 64.5
• 作者: Guo, Xue;Schmiege, Philip;Assafa, Tufa E.;Wang, Rong;Xu, Yan;Donnelly, Linda;Fine, Michael;Ni, Xiaodan;Jiang, Jiansen;Millhauser, Glenn;Feng, Liang;Li, Xiaochun
• 通讯作者: Li, Xiaochun