The Na+/H+ exchanger as a proton regulatory system : its molecular structure and transport mechanism
The Na+/H+ exchanger as a proton regulatory system : its molecular structure and transport mechanism
批准号:
14580664
负责人:
WAKABAYASHI Shigeo
金额:
$2.3万
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (C)
财政年份:
2002
资助国家:
日本
项目状态:
已结题
起止时间:
2002 至 2003
中文摘要
Na~+/H~+交换器(NHEs,SLC9家族)是多种动物体内催化质膜或细胞内细胞膜Na~(++)和H~(++)交换的电子转运体。我们发现,钙调神经磷酸酶B同源蛋白(CHP,其普遍存在的异构体CHP1)通过与质膜型交换异构体NHE1-5的膜旁结构域相互作用,发挥着支持生理活性的重要辅助因子的作用。此外,另一种异构体CHP2在细胞恶性转化时表达,并在维持癌细胞内高pH的过程中发挥作用。我们还分析了CHP的Ca~(2+)与Gt~(2+)结合部位的作用,得出结论:当CHP与NHE1在细胞膜上相互作用时,仍有两个Ca~(2+)~(2+)&Gt~(2+)离子与CHP的EF-手性结合部位结合,并在维持NHE1的生理功能中发挥重要作用。我们通过测量NHE1(^<;22>;Na+从细胞外流)的反向模式反应,在NHE1中发现了这样的额外的H~+结合位点。我们还鉴定了NHE1的关键氨基酸残基(Arg440、Gly455、Gly456),这些氨基酸对调节pH传感器很重要。
英文摘要
The Na^+/H^+ exchanger (NHEs, SLC9 family) are electroneutral transporters that catalyze the exchange of Na^+ and H^+ in plasma membranes or other intracellular organellar membranes in various animal species. We discovered that calcineurin B homologous protein (CHP, its ubiquitous isoform CHP1) functions as an essential cofactor to support the physiological activity by interacting with the juxtamembrane domain of the plasma membrane-type exchanger isoforms NHE1-5. Furthermore, another isoform CHP2 becomes expressed when cells are malignantly transformed and plays a role in maintaining high intracellular pH in cancer cells. We also analyzed the role of Ca^<2+>-binding sites of CHP and concluded that two Ca^<2+> ions remain to be bound to EF-hand binding sites of CHP when interacts with NHE1 in cell membranes and play an important role in maintaining the physiological function of NHE1.In addition to H^+-transport site, H^+-regulatory site have been recognized to be important for pH regulation by NHE1. We discovered such additional H^+-binding sites in NHE1 by measuring the reverse mode reaction of NHE1 (^<22>Na^+ efflux from the cells). We also identified critical amino acid residues (Arg440, Gly455, Gly456) in NHE1 important for regulation of pH-sensor.
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若林繁夫ほか: "Na^+/H^+交換輸送体の構造と機能-活性に必須な因子としてのCHP"心臓. 34. 333-340 (2002)
Shigeo Wakabayashi 等人:“Na^+/H^+ 交换转运蛋白的结构和功能 - CHP 作为活性的重要因素”Heart. 34. 333-340 (2002)
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若林繁夫ほか: "Na^+/H^+交換輸送体:生体プロトン環境を制御するイオントランスポータ"Otology Japan. (印刷中). (2004)
Shigeo Wakabayashi 等人:“Na^+/H^+ 交换转运蛋白:控制生物质子环境的离子转运蛋白”Otology Japan(出版中)。
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Pang, T., Wakabayashi, S., Shigekawa, M.: "Expression of Calcineuin B Homologous Protein 2 Protects Serum Deprivaion-Induced Cell Death by Serum-Independent Activation of Na^+/H^+ exchanger."J.Biol.Chem.. 277. 43771-4377 (2002)
Pang, T.、Wakabayashi, S.、Shigekawa, M.:“钙调蛋白 B 同源蛋白 2 的表达通过 Na^ /H^ 交换器的血清独立激活来保护血清剥夺诱导的细胞死亡。”J.Biol.Chem。
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Pang, T., et al.: "Role of Calcineurin B Homologous Protein in pH Regulation by the Na^+/H^+ Exchanger 1 : Tightly Bound Ca^<2+> Ions as Important Structural Elements."Biochemistry. 43(12). 3628-3636 (2004)
Pang, T., et al.:“钙调神经磷酸酶 B 同源蛋白在 Na^ /H^ 交换器 1 的 pH 调节中的作用:紧密结合的 Ca^<2> 离子作为重要的结构元素。”生物化学。
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Pang, T., et al.: "Expression of Calcineuin B Homologous Protein 2 Protects Serum Deprivalon-Induced Cell Death by Serum-Independent Activation of Na^+/H^+ exchanger."J.Biol.Chem.. 277(46). 43771-43777 (2002)
Pang,T.等人:“钙调蛋白B同源蛋白2的表达通过Na 2 /H 2 交换剂的血清非依赖性激活来保护血清剥夺诱导的细胞死亡。”J.Biol.Chem.. 277(46)。
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共 28 条
Molecular mechanism for regulaiton of ion transporter via lipid signaling and its structural basis
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