p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity
p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity
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DOI：
10.1128/mcb.02246-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Picard, Didier
中科院分区：
文献类型：
--
作者：
Forafonov, Fedor;Toogun, Oyetunji A.;Picard, Didier
分子伴侣Hsp90辅助细胞蛋白的一个子集，在真核生物中是必不可少的。一组伴侣参与和调节多组分Hsp90机器。与cochaperone p23的生化活性不同，其在体内的功能和结构-功能关系仍然知之甚少，即使在遗传上易于处理的模式生物酿酒酵母中也是如此。编码p23同源基因的SBA1基因在该物种中不是必需基因。我们发现，在缺乏p23/Sba1p的情况下，酵母和哺乳动物细胞对Hsp90抑制剂过敏。Sba1p的这种保护功能取决于其结合Hsp90和阻断Hsp90 atp酶和抑制剂结合的能力。相反，Sba1p的保护功能不需要Sba1p独立于hsp90的分子伴侣活性。结构-功能分析表明，Sba1p在与Hsp90结合后发生了相当大的结构重排，p23/Sba1p-Hsp90相互作用表面的大尺寸有助于维持高亲和力，尽管在进化过程中序列分化。在各种微生物可以产生Hsp90抑制化合物的环境中，大界面也可能有助于保持保护功能。
The molecular chaperone Hsp90 assists a subset of cellular proteins and is essential in eukaryotes. A cohort of cochaperones contributes to and regulates the multicomponent Hsp90 machine. Unlike the biochemical activities of the cochaperone p23, its in vivo functions and the structure-function relationship remain poorly understood, even in the genetically tractable model organism Saccharomyces cerevisiae. The SBA1 gene that encodes the p23 ortholog in this species is not an essential gene. We found that in the absence of p23/Sba1p, yeast and mammalian cells are hypersensitive to Hsp90 inhibitors. This protective function of Sba1p depends on its abilities to bind Hsp90 and to block the Hsp90 ATPase and inhibitor binding. In contrast, the protective function of Sba1p does not require the Hsp90-independent molecular chaperone activity of Sba1p. The structure-function analysis suggests that Sba1p undergoes considerable structural rearrangements upon binding Hsp90 and that the large size of the p23/Sba1p-Hsp90 interaction surface facilitates maintenance of high affinity despite sequence divergence during evolution. The large interface may also contribute to preserving a protective function in an environment in which Hsp90 inhibitory compounds can be produced by various microorganisms.