引起疾病的cystathionineβ-synthase链接基因突变损害了全性调节
Joseph V Roman1, Romila Mascarenhas1, Karanfil Ceric1
1Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
The Journal of biological chemistry
|November 10, 2023
概括
囊氨酸β-合成酶 (CBS) 链接区域突变使其结构不稳定,并损害了S-adenosylmethionine (AdoMet) 的调节. 这些发现突显了链接器的作用.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 酶学 是一种酶学.
背景情况:
- 囊氨酸β-合成酶 (CBS) 对于转硫途径至关重要,调节同类半氨酸水平和半氨酸的产生.
- CBS产生硫化 (H2S),这是一个关键的信号分子,并通过S-adenosylmethionine (AdoMet) 进行全激活.
- 在CBS的突变是同胞细胞尿尿症的主要原因,一种代谢障碍.
研究的目的:
- 研究临床变异在CBS左侧区域的结构和功能影响.
- 阐明链接区域在CBS寡合化和全调节中的作用.
主要方法:
- 位于链接区域的三个临床CBS变体 (K384E/N,M391I) 的特征.
- 使用冷电子显微镜 (cryo-EM) 和X射线晶体学分析蛋白质结构.
- 有限的蛋白质分解和稳定状态前的动力学分析,以评估形状变化和酶活性.
主要成果:
- 变种破坏了CBS本源纤维状形式的稳定,并表现出改变的蛋白质溶解指纹,表明了形状变化.
- 截断变体的晶体结构显示,在没有调节域的情况下,催化核心保持完整.
- K384E/N变种显示基底活性显著降低,对AdoMet的反应受损/受抑制,而M391I显示适度下降.
- 动态分析揭示了K384E/N替代物的类效应,特别是影响同类半氨酸结合和反应的下半段.
结论:
- 链接区域对于稳定CBS的高阶结构至关重要.
- 链接区域在调节S-adenosylmethionine (AdoMet) 取决于CBS活动的全调节方面发挥着至关重要的作用.
- 链接区域突变可以通过扰乱CBS结构和功能导致同胞细胞尿性病.
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