人类γ-分泌酶的痕识别的结构基础
Guanghui Yang1, Rui Zhou1, Qiang Zhou1,2
1Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Nature
|January 2, 2019
概括
研究人员揭示了与Notch结合的马分泌酶的结构, 揭示了这种酶如何识别基质. 这一发现解释了癌症中的Notch裂变,并影响了对粉样蛋白前体加工的理解.
科学领域:
- 结构生物学
- 疾病的分子机制
- 神经科学
背景情况:
- 马分泌酶对诺奇受体的异常裂解与各种癌症有关.
- 玛分泌酶识别和结合其基质的确切机制,如Notch,一直是难以捉摸的.
- 了解基质识别对于解读生理和病理背景下的玛分泌酶功能至关重要.
研究的目的:
- 为了确定高分辨率结构的人类玛分泌酶复合的底片段.
- 阐明由玛分泌酶控制基质识别和结合的分子相互作用.
- 对粉样前体蛋白等相关基质的裂变机制及其影响提供结构性见解.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 可视化人类的玛分泌酶/ Notch复合物.
- 在2.7 Å分辨率的高分辨率结构分析.
- 生物化学测试以确认观察到的结构特征的功能意义.
主要成果:
- 诺奇的跨膜螺旋由三种跨膜Presenilin 1 (PS1) 组成,它是玛分泌酶的核心组成部分.
- 在 PS1 中的 Notch 片段的 C 终端 β 链和基质诱导的 β 链之间形成了一个混合的 β 板结构.
- 在基质结合时,PS1经历了显著的形状变化,这表明它在基质结合和裂变中发挥了积极作用.
结论:
- 这项研究揭示了玛分泌酶识别Notch基质的结构基础.
- 裂变发生在 Notch 跨膜螺旋体的 C 端,由混合 β 板促进.
- 这些发现有助于了解玛分泌酶如何与其他基质相互作用,包括粉样蛋白前体,以及开发向治疗方法.
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