Meyer Philippe, Prodromou Chrisostomos, Liao Chunyan, Hu Bin, Roe S Mark, Vaughan Cara K, Vlasic Ignacija, Panaretou Barry, Piper Peter W, Pearl Laurence H
Chester Beatty Laboratories, Section of Structural Biology, The Institute of Cancer Research, London, UK.
EMBO J. 2004 Mar 24;23(6):1402-10. doi: 10.1038/sj.emboj.7600141.
Hsp90 is a molecular chaperone essential for the activation and assembly of many key eukaryotic signalling and regulatory proteins. Hsp90 is assisted and regulated by co-chaperones that participate in an ordered series of dynamic multiprotein complexes, linked to Hsp90 conformationally coupled ATPase cycle. The co-chaperones Aha1 and Hch1 bind to Hsp90 and stimulate its ATPase activity. Biochemical analysis shows that this activity is dependent on the N-terminal domain of Aha1, which interacts with the central segment of Hsp90. The structural basis for this interaction is revealed by the crystal structure of the N-terminal domain (1-153) of Aha1 (equivalent to the whole of Hch1) in complex with the middle segment of Hsp90 (273-530). Structural analysis and mutagenesis show that binding of N-Aha1 promotes a conformational switch in the middle-segment catalytic loop (370-390) of Hsp90 that releases the catalytic Arg 380 and enables its interaction with ATP in the N-terminal nucleotide-binding domain of the chaperone.
热休克蛋白90（Hsp90）是一种分子伴侣，对许多关键的真核信号传导和调节蛋白的激活与组装至关重要。Hsp90由共伴侣蛋白协助并受其调节，这些共伴侣蛋白参与一系列有序的动态多蛋白复合物，与Hsp90构象偶联的ATP酶循环相关。共伴侣蛋白Aha1和Hch1与Hsp90结合并刺激其ATP酶活性。生化分析表明，这种活性依赖于Aha1的N端结构域，该结构域与Hsp90的中央片段相互作用。Aha1的N端结构域（1 - 153，等同于整个Hch1）与Hsp90的中间片段（273 - 530）形成复合物的晶体结构揭示了这种相互作用的结构基础。结构分析和诱变表明，N - Aha1的结合促进了Hsp90中间片段催化环（370 - 390）的构象转换，释放了催化性的精氨酸380，并使其能够与伴侣蛋白N端核苷酸结合结构域中的ATP相互作用。
