设计原则以量身定制Hsp104治疗方法
JiaBei Lin1, Peter J Carman2, Craig W Gambogi2
1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell reports
|December 13, 2024
概括
Hsp104蛋白分解酶的活性是由ATP/ADP结合来调节的. Hsp104-Hsp70相互作用的合理设计为蛋白质病变提供了治疗潜力.
科学领域:
- 分子生物学分子生物学
- 蛋白质生物化学 蛋白质生物化学
- 生物物理学的生物物理.
背景情况:
- 六方体AAA+解聚酶Hsp104通过与Hsp70和Hsp40护航者合作,使聚合蛋白质溶解.
- 通过Hsp104中域 (MD) 的ATP或ADP结合状态来调节其六大功能和伴侣相互作用的精确机制尚未完全理解.
研究的目的:
- 通过ATP/ADP特定的中间域配置阐明Hsp104调节的结构基础.
- 研究这些配置如何调节与Hsp70和Hsp40.0的相互作用.
- 为治疗应用制定设计原则,以量身定制Hsp104活动.
主要方法:
- 生物化学测试以评估Hsp104分聚酶活性和伴侣相互作用.
- 结构分析来定义核酸特异性蛋白质-蛋白质接触网络.
- 现场定向突变发生和合理设计来操纵Hsp104-Hsp70合作.
- 基于细胞的测试,以评估工程Hsp104变体在抵消蛋白质病变方面的有效性.
主要成果:
- 确定了NBD1和MD螺旋L1之间的ATP特异性互原体接触网络,调整了HSP70的协作.
- 扰乱这个网络产生了变体,改变了Hsp70/Hsp40协作,包括Hsp70独立的和B类Hsp40选择性的形式.
- 在MD螺旋L2和NBD1之间的ADP特异性内原体接触限制了活性;它们的干扰增强了Hsp104.4.
- NBD1:MD螺旋 L1 接口的合理设计允许微调 Hsp70 协作,从而使 Hsp104 活动具有最大限度的毒性.
结论:
- 结构洞察力揭示了ATP/ADP状态如何决定Hsp104六合体动力学和伴侣相互作用.
- 针对NBD1:MD螺旋L1接口的定向调制提供了一个安全的HSP104增强的策略.
- 工程Hsp104变种显示出治疗FUS和TDP-43蛋白病变的希望,为基于Hsp104的治疗方法建立了设计原则.
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