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冷冻电镜结构揭示了INDY的H/柠檬酸盐同向转运机制。

Cryo-EM structures reveal the H/citrate symport mechanism of INDY.

作者信息

Kim Subin, Park Jun Gyou, Choi Seung Hun, Kim Ji Won, Jin Mi Sun

机构信息

School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.

Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.

出版信息

Life Sci Alliance. 2025 Jan 30;8(4). doi: 10.26508/lsa.202402992. Print 2025 Apr.

DOI:10.26508/lsa.202402992
PMID:39884835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11782487/
Abstract

I'm Not Dead Yet (INDY) functions as a transporter for citrate, a key metabolite in the citric acid cycle, across the plasma membrane. Partial deficiency of INDY extends lifespan, akin to the effects of caloric restriction. In this work, we use cryo-electron microscopy to determine structures of INDY in the presence and absence of citrate and in complex with the well-known inhibitor 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) at resolutions ranging from 2.7 to 3.6 Å. Together with functional data obtained in vitro, the INDY structures reveal the H/citrate co-transport mechanism, in which aromatic residue F119 serves as a one-gate element. They also provide insight into how protein-lipid interactions at the dimerization interface affect the stability and function of the transporter, and how DIDS disrupts the transport cycle.

摘要

“我还没死”（INDY）作为柠檬酸（三羧酸循环中的关键代谢物）穿过质膜的转运体发挥作用。INDY的部分缺陷可延长寿命，类似于热量限制的效果。在这项研究中，我们使用冷冻电子显微镜在有和没有柠檬酸存在的情况下以及与著名抑制剂4,4'-二异硫氰酸-2,2'-二磺酸芪（DIDS）形成复合物的情况下，以2.7至3.6 Å的分辨率确定INDY的结构。结合体外获得的功能数据，INDY结构揭示了H/柠檬酸共转运机制，其中芳香族残基F119作为单门元件。它们还深入了解了二聚化界面处的蛋白质-脂质相互作用如何影响转运体的稳定性和功能，以及DIDS如何破坏转运循环。

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本文引用的文献

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Substrate translocation and inhibition in human dicarboxylate transporter NaDC3.人二羧酸转运体NaDC3中的底物转运与抑制
Nat Struct Mol Biol. 2025 Mar;32(3):502-512. doi: 10.1038/s41594-024-01433-0. Epub 2024 Dec 2.
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Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism.冷冻电镜结构解析揭示了人源 NaS1 和 NaDC1 转运体的“电梯式”转运及别构调控机制。
Sci Adv. 2024 Mar 29;10(13):eadl3685. doi: 10.1126/sciadv.adl3685.
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Ion and lipid orchestration of secondary active transport.
离子和脂质对次级主动转运的调控。
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Structural basis of ion - substrate coupling in the Na-dependent dicarboxylate transporter VcINDY.Na 依赖性二羧酸转运蛋白 VcINDY 中离子-底物偶联的结构基础。
Nat Commun. 2022 May 12;13(1):2644. doi: 10.1038/s41467-022-30406-4.
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INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions.INDY与哺乳动物INDY：尽管生物学功能大多相似，但在转运机制和结构特征上存在重大差异。
Metabolites. 2021 Sep 29;11(10):669. doi: 10.3390/metabo11100669.
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Structure and inhibition mechanism of the human citrate transporter NaCT.人源柠檬酸转运蛋白 NaCT 的结构与抑制机制。
Nature. 2021 Mar;591(7848):157-161. doi: 10.1038/s41586-021-03230-x. Epub 2021 Feb 17.
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3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM.3D 变异性分析：从单颗粒冷冻电镜中解析连续的柔韧性和离散的异质性。
J Struct Biol. 2021 Jun;213(2):107702. doi: 10.1016/j.jsb.2021.107702. Epub 2021 Feb 11.
8
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JCI Insight. 2021 Jan 25;6(2):136083. doi: 10.1172/jci.insight.136083.
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Functional analysis of a species-specific inhibitor selective for human Na+-coupled citrate transporter (NaCT/SLC13A5/mINDY).一种针对人源 Na+-偶联枸橼酸盐转运蛋白（NaCT/SLC13A5/mINDY）具有选择性的物种特异性抑制剂的功能分析。
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