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客户端从BiP加载到Grp94的机制及其被选择性抑制剂破坏

Tara P Azam¹, Luna Han¹, Erin E Deans¹

¹Department of Biochemistry at Brandeis University, Waltham, MA, 02453, USA.

Nature communications

|April 15, 2025

概括

热冲击蛋白90 (Hsp90) 抑制剂会影响客户端蛋白质的负载. 一些Hsp90抑制剂破坏了加载过程,为癌症药物设计提供了新的策略.

科学领域:

分子生物学分子生物学
癌症生物学癌症生物学
结构生物学结构生物学

背景情况:

热冲击蛋白90 (Hsp90) 是一个关键的分子伴侣和一个验证的癌症药物标.
许多ATP竞争性Hsp90抑制剂正在进行癌症治疗的临床试验.
通过Hsp90抑制剂影响客户端蛋白转移和加载的精确机制仍然不完全理解.

研究的目的:

为了研究Hsp90抑制剂如何影响客户端蛋白质的输送,加载和捕获步骤.
阐明 Hsp70 陪伴器 BiP 在促进客户端加载到 Hsp90 平行模拟器 Grp94.4 上的作用.
确定控制抑制剂对Hsp90客户端负载的影响的结构性决定因素.

主要方法:

在不同Hsp90抑制剂的存在下对ER居住的BiP/Grp94护卫系统 (Hsp70/Hsp90对应物) 的比较分析.
生物化学试验检查Grp94.4中的BiP介导的构造变化.
结构研究以了解抑制剂相互作用及其对三元复合体形成的影响.

主要成果:

特定的Hsp90抑制剂差异调节BiP诱导Grp94.4的客户端负载构造的能力.
某些抑制剂阻断BiP驱动的结构变化,导致BiP/客户端/Grp94三元复合物的不稳定.
通过Hsp90抑制剂的一个子集确定了选择性抑制客户端负载的结构基础.

结论:

BiP 通过 ER 和细胞质 Hsp70/Hsp90 系统之间保留的机制,积极驱动 Grp94 进入客户端负载能力状态.
了解这些客户端加载动态揭示了特定抑制剂如何破坏Hsp90功能.
这些发现为开发新的,合理设计的针对Hsp90的癌症疗法提供了基础.

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