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人类ACAT1的催化结构基础和基质特异性

Hongwu Qian¹, Xin Zhao², Renhong Yan^3,4

¹Department of Molecular Biology, Princeton University, Princeton, NJ, USA. hongwuq@princeton.edu.

|May 21, 2020

概括

研究人员阐明了人类ACAT1的结构, 结构揭示了基质进入的道,为其催化机制和基质偏好提供了洞察力.

科学领域:

生物化学
结构生物学
酵素学

背景情况:

乙烯共酶A:胆固醇乙烯转移酶 (ACAT) 是胆固醇稳态中的关键酶,属于膜结合的O-乙烯转移酶 (MBOAT) 族.
ACATs催化胆固醇的形成,对于细胞胆固醇的储存和运输至关重要.
ACAT被认为是动脉样硬化,阿尔茨海默病和癌症的治疗点.

研究的目的:

使用冷电子显微镜确定人类ACAT1的高分辨率结构.
阐明ACAT1的酶活性和基质特异性的结构基础.
提供关于ACAT1和其他MBOAT家族酶的催化机制的见解.

主要方法:

低温电子显微镜 (cryo-EM) 来确定人类ACAT1的结构.
二次结构的四次结构分析.
结构引导的突变分析以探测基质进入途径.

主要成果:

人类ACAT1的冷EM结构被分解为二元体的二元体.
每个原质体包括九个跨膜段,形成不同的细胞和跨膜道.
这些道汇聚在活性部位,表明乙辅酶A (细胞道) 和胆固醇 (跨膜道) 的单独入口路径.
生物化学数据合理化了ACAT1对不和链的偏好.

结论:

确定的结构为了解ACAT1功能提供了分子框架.
已识别的基质进入道为ACAT1催化提供了机械洞察力.
这项研究促进了我们对胆固醇代谢的理解,并为针对ACAT1的合理药物设计提供了基础.

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