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哺乳动物谷氨基素中囊蛋白的结构和功能精细映射揭示了它们的不同氧化易感性

Elizabeth M Corteselli¹, Mona Sharafi², Robert Hondal³

¹Department of Pathology and Laboratory of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, 05405, USA.

Nature communications

|July 28, 2023

概括

谷氨基素 (GLRX) 保护蛋白质S-谷氨基化,但可以通过囊氧化变得不活跃. 这项研究确定了易受氧化影响的关键囊蛋白 (C8,C83),揭示了增强GLRX稳定性和治疗潜力的策略.

科学领域:

生物化学生物化学
分子生物学分子生物学
氧化压力研究研究氧化压力研究

背景情况:

蛋白质S-谷氨基化,是一种由谷氨基对蛋白质硫醇的可逆修饰,调节细胞蛋白质的功能.
谷氨基素 (GLRX) 是关键的氧化还原酶,可以逆转S-谷氨基化,维持细胞的氧化还原平衡.
GLRX 具有五种易受氧化损伤的氨酸残留物,导致聚合和酶活性丧失.

研究的目的:

为了确定GLRX中容易发生氧化修饰和聚合的特定的氨酸残留物.
阐明单个囊蛋白在GLRX二聚体形成,聚合和氧化易感性中的作用.
探索增强GLRX活性和抗氧化压力的稳定性的策略.

主要方法:

在基分子建模中预测囊的脆弱性.
在体外活性测定使用重组GLRX.
单个和组合的氨酸残留物的局部定向突变发生.
过氧化诱导的氧化试验.

主要成果:

氨酸C8和C83被确定为S-氨基化和过氧化诱导的氧化在体外的主要标.
分子建模和实验数据证实了C8在GLRX二聚体形成和聚合中的重要作用.
对C8,C26和C83的组合突变产生了具有增强活性和抗氧化失活和聚合的GLRX变体.

结论:

在GLRX中的特定囊蛋白 (C8,C83) 是其氧化易感性和聚合的关键决定因素.
这些囊蛋白的向突变发生可以显著提高GLRX的稳定性和治疗疗效.
了解GLRX氨酸氧化,为改变蛋白质谷氨基化条件下的治疗干预提供了洞察力.

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