Steroid receptor interactions with heat shock protein and immunophilin chaperones.
Steroid receptor interactions with heat shock protein and immunophilin chaperones.
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DOI：
10.1210/edrv.18.3.0303
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发表时间：
1997-06
影响因子：
20.3
通讯作者：
W. Pratt;D. Toft
中科院分区：
文献类型：
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作者：
W. Pratt;D. Toft
我们已经提供了一个历史的角度对类固醇受体的研究机构处理的结构和生理意义的未转化的9 S受体，经常混淆新手和专家调查。早期研究中经常出现的争议和模棱两可是由于这些受体的天然无蛋白状态是一个大的多蛋白复合物，由于其不稳定和动态的性质，多年来一直无法描述。类固醇和二恶英受体的未转化的9 S状态为研究普遍存在的、丰富的和保守的热休克蛋白HSP 90的功能提供了独特的系统。与热休克蛋白90受体协会的激素控制提供了一种方法，操纵受体异源复合物的方式是生理上有意义的。对于几种类固醇受体，结合到热休克蛋白90是需要的受体是在一个天然的hsp 90结合状态，并为所有的受体，激素结合促进解离的受体从热休克蛋白90和转换的受体的DNA结合状态。虽然酪氨酸激酶和热休克蛋白90之间的复合物被发现较早，激素调节或类固醇受体与热休克蛋白90协会允许更快速和更容易的研究热休克蛋白90的功能。hsp 90通过其HBD与受体结合，并且这些结构域可以与结构不同的蛋白质融合，使其功能受到激素控制，这一观察结果提供了受体与hsp 90结合的激素调节与类固醇激素作用的初始步骤之间的有力联系。由于9 S受体hsp 90杂合物可以通过双磷酸盐物理稳定，因此可以容易地研究它们的蛋白质组成，并且很明显这些复合物是含有许多独特蛋白质的多蛋白质结构，例如FKBP 51，FKBP 52，CyP-40和p23，这些蛋白质是因为它们在这些结构中的存在而被发现的。进一步的分析表明，热休克蛋白90本身存在于各种天然的多蛋白杂合物的类固醇受体和其他“底物”蛋白的独立。无细胞系统现在可用于研究受体杂合物的形成。正如我们在图1的示意图中所概述的，多组分受体-hsp 90异源复合物组装系统正在重建，并且单个蛋白质（例如hsp 70、p60和p23）在组装过程中的重要性正在被认识到。应该指出的是，我们对类固醇受体异源复合物组装的机制和目的的理解仍处于早期阶段。我们现在可以推测受体相关蛋白在受体作用中的作用，无论是作为个体还是作为一个群体，但它们的实际功能仍然模糊或未知。我们可以制作关于类固醇受体的陪伴和运输的现实模型，但我们还不知道这些过程是如何发生的，我们不知道陪伴在细胞中发生的位置（例如，它是否仅限于细胞质？它是一个扩散的过程还是伴随着结构元件发生？），而且，除了激素结合的需要外，我们不知道基于hsp 90的伴侣系统对类固醇激素作用的影响程度。目前还不清楚这种hsp 90异源复合物组装系统的发现将在多大程度上扩展到对细胞中蛋白质加工的一般理解。因为这种装配系统显然存在于所有真核细胞中，所以它可能对许多蛋白质执行基本功能。hsp 90的细菌同源物不是必需蛋白质，但hsp 90在真核生物中是必需的，最近的研究表明，原核祖细胞的细胞核发育伴随着hsp 90和hsp 70基因的复制（698）。（摘要截断）
We have provided a historical perspective on a body of steroid receptor research dealing with the structure and physiological significance of the untransformed 9S receptor that has often confused both novice and expert investigators. The frequent controversies and equivocations of earlier studies were due to the fact that the native, hormone-free state of these receptors is a large multiprotein complex that resisted description for many years because of its unstable and dynamic nature. The untransformed 9S state of the steroid and dioxin receptors has provided a unique system for studying the function of the ubiquitous, abundant, and conserved heat shock protein, hsp90. The hormonal control of receptor association with hsp90 provided a method of manipulating the receptor heterocomplex in a manner that was physiologically meaningful. For several steroid receptors, binding to hsp90 was required for the receptor to be in a native hormone-binding state, and for all of the receptors, hormone binding promoted dissociation of the receptor from hsp90 and conversion of the receptor to the DNA-binding state. Although the complexes between tyrosine kinases and hsp90 were discovered earlier, the hormonal regulation or steroid receptor association with hsp90 permitted much more rapid and facile study of hsp90 function. The observations that hsp90 binds to the receptors through their HBDs and that these domains can be fused to structurally different proteins bringing their function under hormonal control provided a powerful linkage between the hormonal regulation of receptor binding to hsp90 and the initial step in steroid hormone action. Because the 9S receptor hsp90 heterocomplexes could be physically stabilized by molybdate, their protein composition could be readily studied, and it became clear that these complexes are multiprotein structures containing a number of unique proteins, such as FKBP51, FKBP52, CyP-40, and p23, that were discovered because of their presence in these structures. Further analysis showed that hsp90 itself exists in a variety of native multiprotein heterocomplexes independent of steroid receptors and other 'substrate' proteins. Cell-free systems can now be used to study the formation of receptor heterocomplexes. As we outlined in the scheme of Fig. 1, the multicomponent receptor-hsp90 heterocomplex assembly system is being reconstituted, and the importance of individual proteins, such as hsp70, p60, and p23, in the assembly process is becoming recognized. It should be noted that our understanding of the mechanism and purpose of steroid receptor heterocomplex assembly is still at an early stage. We can now speculate on the roles of receptor-associated proteins in receptor action, both as individuals and as a group, but their actual functions are still vague or unknown. We can make realistic models about the chaperoning and trafficking of steroid receptors, but we don't yet know how these processes occur, we don't know where chaperoning occurs in the cell (e.g. Is it limited to the cytoplasm? Is it a diffuse process or does chaperoning occur in association with structural elements?), and, with the exception of the requirement for hormone binding, we don't know the extent to which the hsp90-based chaperone system impacts on steroid hormone action. It is not yet clear how far the discovery of this hsp90 heterocomplex assembly system will be extended to the development of a general understanding of protein processing in the cell. Because this assembly system is apparently present in all eukaryotic cells, it probably performs an essential function for many proteins. The bacterial homolog of hsp90 is not an essential protein, but hsp90 is essential in eukaryotes, and recent studies indicate that the development of the cell nucleus from prokaryotic progenitors was accompanied by the duplication of genes for hsp90 and hsp70 (698). (ABSTRACT TRUNCATED)