在非正规部位的Pin1催化普罗林cis-trans异构的基础上存在一种连接机制
Christopher C Williams1,2, Jonathan Chuck1,2, Paola Munoz-Tello3
1Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, FL 33458.
概括
益醇异构酶Pin1酶通过连接机制结合PPARγ,使其能够在非正规位点催化异构化. 这揭示了Pin1的新型号.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 酶学 是一种酶学.
背景情况:
- 烯基异构酶Pin1通过林键异构化调节细胞过程.
- Pin1有一个WW域用于酸化基因和一个PPIase域用于催化.
- 像PPARγ这样的核受体在基因调节中起着至关重要的作用.
研究的目的:
- 研究人类核受体PPARγ上的Pin1结合和催化机制.
- 为了阐明Pin1在通过proline异构化调节PPARγ功能的作用.
- 改进对Pin1的催化机制的理解,特别是与非正规的动机.
主要方法:
- 核磁共振 (NMR) 谱学用于识别结合点和动态.
- 在体外激酶试验 (ERK2酸化).
- 细胞转录试验,突变发生和Pin1抑制剂研究.
主要成果:
- Pin1通过正规 (pS112-P113) 和非正规 (W39-P40) 动机结合PPARγ的AF-1域.
- Pin1加速非正规的W39-P40图案的 cis-trans 异构化.
- 通过Pin1介导的W39-P40的异构化对PPARγ转录活性具有功能意义.
结论:
- Pin1利用一个绑定机制,使用其WW域绑定一个正规的动机,并将其PPIase域定位到一个偏远的非正规位点进行催化.
- 这项研究揭示了一种新的Pin1作用模式,并扩大了已知的基质和机制的范围.
- 这些发现提供了通过翻译后修改和异构酶对核受体功能的调节的见解.
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