底物结合驱动 Hsp90 分子伴侣的大规模构象变化。
Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone.
机构信息
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158-2517, USA.
出版信息
Mol Cell. 2011 Apr 8;42(1):96-105. doi: 10.1016/j.molcel.2011.01.029.
Hsp90 is a ubiquitous molecular chaperone. Previous structural analysis demonstrated that Hsp90 can adopt a large number of structurally distinct conformations; however, the functional role of this flexibility is not understood. Here we investigate the structural consequences of substrate binding with a model system in which Hsp90 interacts with a partially folded protein (Δ131Δ), a well-studied fragment of staphylococcal nuclease. SAXS measurements reveal that under apo conditions, Hsp90 partially closes around Δ131Δ, and in the presence of AMPPNP, Δ131Δ binds with increased affinity to Hsp90's fully closed state. FRET measurements show that Δ131Δ accelerates the nucleotide-driven open/closed transition and stimulates ATP hydrolysis by Hsp90. NMR measurements reveal that Hsp90 binds to a specific, highly structured region of Δ131Δ. These results suggest that Hsp90 preferentially binds a locally structured region in a globally unfolded protein, and this binding drives functional changes in the chaperone by lowering a rate-limiting conformational barrier.
热休克蛋白 90（Hsp90）是一种普遍存在的分子伴侣。先前的结构分析表明，Hsp90 可以采用多种结构上不同的构象；然而，这种灵活性的功能作用尚不清楚。在这里，我们使用模型系统研究了底物结合对结构的影响，该模型系统中 Hsp90 与部分折叠的蛋白质（Δ131Δ）相互作用，而 Δ131Δ 是葡萄球菌核酸酶的一个研究充分的片段。小角 X 射线散射（SAXS）测量结果表明，在没有核苷酸的情况下，Hsp90 部分地围绕 Δ131Δ 闭合，而在 AMPPNP 的存在下，Δ131Δ 以增加的亲和力结合到 Hsp90 的完全闭合状态。荧光共振能量转移（FRET）测量结果表明，Δ131Δ 加速了核苷酸驱动的开/闭构象转变，并刺激了 Hsp90 的 ATP 水解。NMR 测量结果表明，Hsp90 结合到 Δ131Δ 的一个特定的、高度结构化的区域。这些结果表明，Hsp90 优先结合在全局展开的蛋白质中具有局部结构的区域，这种结合通过降低限速构象障碍来驱动伴侣蛋白的功能变化。
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