Chaperoning of glucocorticoid receptors.
Chaperoning of glucocorticoid receptors.
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DOI：
10.1007/3-540-29717-0_5
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发表时间：
2006
影响因子：
--
通讯作者：
W. Pratt;Y. Morishima;M. Murphy;M. Harrell
中科院分区：
文献类型：
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作者：
W. Pratt;Y. Morishima;M. Murphy;M. Harrell
以HSP90/HSP70为基础的多蛋白分子伴侣机制作为调节糖皮质激素受体(GR)的类固醇结合、运输和周转的“摇篮-坟墓”系统发挥作用。在一个依赖于ATP的过程中，HSP70和HSP90作为基本伴侣，Hop、Hsp40和p23作为非必要辅助伴侣，机械组装GR和HSP90的配体结合域之间的复合体。在GR-HSP90异源复合体的组装过程中，疏水的配体结合裂隙被类固醇打开，随后类固醇在裂隙内的结合触发了受体的转变，使其参与到与HSP90的更动态的组装/拆解循环中，这是快速动力蛋白依赖的移位到细胞核所必需的。在细胞核内，HSP90分子伴侣机制在GR向转录调控部位的转移和激素水平下降时调控复合体的分解过程中都起着关键作用。伴侣机制在GR到泛素化和蛋白酶体降解的稳定中也起着关键作用。最初的GR与HSP70的相互作用对于HSP90异源复合体组装和受体功能的保存与依赖于芯片的泛素化和蛋白酶体降解之间的权衡至关重要。HSP90的伴侣机制在真核生物中普遍存在，并且在功能上是保守的，而且HSP90的所有重要生理作用都可能需要依赖于HSP70的客户蛋白-HSP90异源复合体的组装。
A multiprotein hsp90/hsp70-based chaperone machinery functions as a ‘cradleto-grave’ system for regulating the steroid binding, trafficking and turnover of the glucocorticoid receptor (GR). In an ATP-dependent process where hsp70 and hsp90 act as essential chaperones and Hop, hsp40, and p23 act as nonessential co-chaperones, the machinery assembles complexes between the ligand binding domain of the GR and hsp90. During GR-hsp90 heterocomplex assembly, the hydrophobic ligand-binding cleft is opened to access by steroid, and subsequent binding of steroid within the cleft triggers a transformation of the receptor such that it engages in more dynamic cycles of assembly/disassembly with hsp90 that are required for rapid dynein-dependent translocation to the nucleus. Within the nucleus, the hsp90 chaperonemachinery plays a critical role both in GR movement to transcription regulatory sites and in the disassembly of regulatory complexes as the hormone level declines. The chaperone machinery also pays a critical role in stabilization of the GR to ubiquitylation and proteasomal degradation. The initial GR interaction with hsp70 appears to be critical for the triage between hsp90 heterocomplex assembly and preservation of receptor function vs CHIP-dependent ubiquitylation and proteasomal degradation. The hsp90 chaperone machinery is ubiquitous and functionally conserved among eukaryotes, and it is possible that all physiologically significant actions of hsp90 require the hsp70-dependent assembly of client protein-hsp90 heterocomplexes.