Structure and Function of SWEET Sugar Transporters

SWEET糖转运蛋白的结构和功能

• 批准号: 10219289
• 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/10219289
• 关键词: Affect; Amino Acids; Biological Process; Carbon; Communication; Complex; Coupled; Coupling; Cryoelectron Microscopy; Crystallization; 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; cancer type; conformational conversion; disease-causing mutation; improved; insight; member; novel; pathogen; 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. !

项目摘要 在过去的十年中，研究发现了大型的生理重要性和疾病相关性 膜转运蛋白/受体超家族，称为MTN3家族。例如，甜品转运蛋白至关重要 用于糖出水和利用； PQ-loop转运蛋白已与囊肿和斑岩疾病有关。这 线粒体丙酮酸载体控制中央代谢途径的临界分支点，并与 在癌症中； KDEL受体对于内质网质量控制至关重要，并且已经关联 患有扩张的心肌病。尽管这些功能多样而重要，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和机械 阐明跨膜运输的物理基础并阐明生理的见解 MTN3转运蛋白的功能和引起疾病的功能故障。我们将专注于甜糖转运蛋白， MTN3家族的创始成员，然后将我们的工作扩展到包括相关运输者家庭。在 我们先前的研究，我们在内向和高分辨率的状态下解决了第一个真核生物甜结构 多种构象状态中细菌半甜的结构，阐明了糖的传输 糖果和交替的访问机制更广泛。这些结果为进一步提供了坚实的基础 探测MTN3转运蛋白的机制。在此续订应用程序中，我们建议将此工作扩展到：（1） 阐明串扰的结构基础和真核甜味的交替进入； （2）剖析基板 甜味转运蛋白的选择性； （3）确定PQ-LOOP转运蛋白的结构基础。 了解MTN3转运蛋白如何在分子水平上工作将为其运输提供丰富的见解 机制和串扰。此外，这项工作将提供一个蓝图，以了解PQ-loop的功能 转运蛋白并揭示破坏溶酶体储存疾病的机制。最终，我们的工作 将产生基本知识，以促进针对治疗剂的MTN3。 呢