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. !

项目概要 过去十年的研究揭示了大量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，SWEET 转运蛋白至关重要 用于糖的流出和利用； PQ 环转运蛋白与胱氨酸病和巴顿病有关；这 线粒体丙酮酸载体控制着中央代谢途径的关键分支点并与之相关 在癌症中； KDEL 受体对于内质网质量控制至关重要，并且与 患有扩张型心肌病。尽管有这些多样化且重要的功能，但我们对它仍然知之甚少。 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学的见解 MtN3 转运蛋白的功能和致病故障。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的转运蛋白家族。在 在我们之前的研究中，我们解决了第一个处于向内开放状态和高分辨率的真核SWEET结构 多种构象状态的细菌半糖的结构，揭示了糖的运输 SWEET 和更广泛的交替访问机制。这些成果为进一步开展 探究 MtN3 转运蛋白的机制。在此续展申请中，我们建议将这项工作扩展到：(1) 阐明真核SWEET串扰和交替访问的结构基础； (2) 解剖基板 SWEET 转运蛋白的选择性； (3)确定PQ环转运蛋白的结构基础。 了解 MtN3 转运蛋白如何在分子水平上发挥作用将为了解其转运提供丰富的见解 机制和串扰。此外，这项工作将为理解 PQ-loop 的功能提供一个蓝图 转运蛋白并揭示破坏性溶酶体贮积病的潜在机制。最终，我们的工作 将产生有助于靶向 MtN3 进行治疗的重要知识。 ！