人类乙-CoA碳酸酶调节的结构基础
Moritz Hunkeler1,2, Anna Hagmann3, Edward Stuttfeld3
1Biozentrum, University of Basel, Basel, Switzerland. moritz_hunkeler@dfci.harvard.edu.
Nature
|June 15, 2018
概括
研究人员发现了乙-CoA碳酸酶1 (ACC1) 如何形成细丝来调节脂肪酸生物合成. 酸盐会激活ACC1纤维,而BRCA1结合则会使其失活,从而揭示出一种新的酶调节机制.
科学领域:
- 生物化学
- 结构生物学
- 酵素学
背景情况:
- 乙-CoA碳酶 (ACC) 是脂肪酸生物合成中的关键酶,催化了依赖ATP的乙-CoA碳化.
- 人类的ACC存在两种异型,即ACC1 (细胞) 和ACC2 (线粒体),其中ACC1调节脂肪酸合成.
- ACC1的调节涉及酸化,效因子和蛋白质相互作用,往往导致丝的形成,但结构基础仍然难以捉摸.
研究的目的:
- 阐明乙-CoA碳酸酶1 (ACC1) 聚合的结构基础及其调节.
- 识别不同的激活和抑制的ACC1导线结构.
- 通过大规模的形状变化了解酶调节的机制.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定ACC1丝的结构.
- 通过酸盐进行研究.
- 研究了BRCA1的BRCT域的抑制.
主要成果:
- 鉴定出不同的激活型 (ACC- 酸盐) 和抑制型 (ACC1- BRCA1) ACC1导线形式.
- 冷电磁结构揭示了这些独特的丝状状态的分子基础.
- 导线形成将ACC1锁定到特定的构造状态,影响催化活性.
结论:
- 发光线形成是ACC1的关键调节机制,可以在催化活性和非活性状态之间切换.
- 这通过大规模的形状变化提供了对ACC1调节的结构理解.
- 对ACC1调控的洞察可能为与高调控脂肪酸生物合成相关的疾病提供新的治疗策略.
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