The co-chaperone Hch1 regulates Hsp90 function differently than its homologue Aha1 and confers sensitivity to yeast to the Hsp90 inhibitor NVP-AUY922.
The co-chaperone Hch1 regulates Hsp90 function differently than its homologue Aha1 and confers sensitivity to yeast to the Hsp90 inhibitor NVP-AUY922.
复制标题
共伴侣HCH1调节HSP90的功能不同于其同源物AHA1，并且对酵母对HSP90抑制剂NVP-AUY922的敏感性赋予了敏感性。
DOI：
10.1371/journal.pone.0049322
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
LaPointe P
中科院分区：
文献类型：
--
作者：
Armstrong H;Wolmarans A;Mercier R;Mai B;LaPointe P
Hsp90 是一种二聚体 ATP 酶，负责一组称为“客户”的特定底物蛋白的激活或成熟。这种分子伴侣在涉及 ATP、共伴侣蛋白和客户的结构动态和高度调控的循环背景下发挥作用。共伴侣蛋白调节构象转变，这种转变可能在 Hsp90 突变形式中受到损害。我们在此报告，共同伴侣 Hch1p 加剧了通常研究的含有 G313S 或 A587T 突变的 Hsp90 变体的体内损伤。删除 HCH1（而非 AHA1）可减轻在表达这两种 Hsp90 变体的酿酒酵母中观察到的温度敏感表型和对 Hsp90 抑制剂药物的高敏感性。此外，HCH1 的缺失导致表达野生型 Hsp90 的酵母对 Hsp90 抑制剂具有高抗性。相反，Hch1p 的过表达大大增加了表达野生型 Hsp90 的酵母对 Hsp90 抑制的敏感性。我们的结论是，尽管这两个共伴侣之间存在相似性，但 Hch1p 和 Aha1p 以不同的方式调节 Hsp90 功能，并且可能与其作为 ATP 酶刺激剂的作用无关。我们进一步得出结论，Hch1p 在调节酵母中 Hsp90 抑制剂药物敏感性中发挥着关键作用。
Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed ‘clients’. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast.
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NVP-AUY922：一种小分子 HSP90 抑制剂，在临床前乳腺癌模型中具有有效的抗肿瘤活性。
DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jensen MR;Schoepfer J;Radimerski T;Massey A;Guy CT;Brueggen J;Quadt C;Buckler A;Cozens R;Drysdale MJ;Garcia-Echeverria C;Chène P
通讯作者：
Chène P
影响因子：
5.3
作者：
Hawle, Patricija;Siepmann, Martin;Obermann, Wolfgang M. J.
通讯作者：
Obermann, Wolfgang M. J.
影响因子：
3.2
作者：
ITO, H;FUKUDA, Y;KIMURA, A
通讯作者：
KIMURA, A
影响因子：
5.3
作者：
Johnson, Jill L.;Halas, Agnieszka;Flom, Gary
通讯作者：
Flom, Gary
影响因子：
3.3
作者：
Flom, G;Weekes, J;Johnson, JL
通讯作者：
Johnson, JL