Pratt W B
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Proc Soc Exp Biol Med. 1998 Apr;217(4):420-34. doi: 10.3181/00379727-217-44252.
A variety of transcription factors and protein kinases involved in signal transduction are recovered from cells in heterocomplexes containing the abundant protein chaperone hsp90. Genetic studies in yeast have demonstrated that binding of steroid receptors, the dioxin receptor, and some protein kinases to hsp90 is critical for their signal transducing function in vivo. These heterocomplexes are formed by a multiprotein chaperone machinery consisting of at least four ubiquitous proteins--hsp90, hsp70, p60 and p23. Four high-molecular-weight immunophilins have been discovered as components of steroid receptor or other transcription factor complexes with hsp90. The immunophilins, protein chaperones with prolyl isomerase activity, bind the immunosuppressant drugs FK506 or CyP-40. These immunophilins all bind via tetratricopeptide repeat (TPR) domains to a single TPR binding site on each hsp90 dimer, and multiple heterocomplexes exist for each protein chaperoned by hsp90 according to the immunophilin that is bound to this TPR binding site at any time. Three components of the MAP kinase signalling system (Src, Raf, and Mek) exist in complexes with hsp90 and a 50-kDa protein that is the mammalian homolog of the yeast cell cycle control protein cdc37. The p50cdc37 binds to hsp90 at a site that is close to but different from the TPR binding site of the immunophilins, and like the immunophilins, p50cdc37 is thought to be involved in targeting and trafficking of the protein kinases. The recent introduction of the benzoquinone antibiotic geldanamycin has facilitated the identification of proteins that are chaperoned by the hsp90-based system. Geldanamycin binds to members of the hsp90 protein family, blocking assembly of hsp90 heterocomplexes and destabilizing preformed heterocomplexes. In the presence of geldanamycin, the function of hsp90-chaperoned proteins is disrupted, and the proteins undergo rapid degradation by an ubiquitin-dependent proteasomal mechanism. It is becoming clear that hsp90 chaperoning is not only essential to a variety of signal transduction pathways, but is critical for proper folding, stabilization, and trafficking of an expanding list of proteins.
在含有丰富的蛋白质伴侣hsp90的异源复合物中，可从细胞中回收多种参与信号转导的转录因子和蛋白激酶。酵母中的遗传学研究表明，类固醇受体、二恶英受体和一些蛋白激酶与hsp90的结合对于它们在体内的信号转导功能至关重要。这些异源复合物是由一种多蛋白伴侣机制形成的，该机制至少由四种普遍存在的蛋白质组成——hsp90、hsp70、p60和p23。已发现四种高分子量亲免蛋白是类固醇受体或其他转录因子与hsp90复合物的组成成分。亲免蛋白是具有脯氨酰异构酶活性的蛋白质伴侣，可结合免疫抑制剂药物FK506或CyP - 40。这些亲免蛋白均通过四肽重复（TPR）结构域与每个hsp90二聚体上的单个TPR结合位点结合，并且对于hsp90所陪伴的每种蛋白质，根据随时与该TPR结合位点结合的亲免蛋白的不同，存在多种异源复合物。丝裂原活化蛋白激酶（MAP）信号系统的三个组分（Src、Raf和Mek）存在于与hsp90以及一种50 kDa蛋白质形成的复合物中，该50 kDa蛋白质是酵母细胞周期控制蛋白cdc37的哺乳动物同源物。p50cdc37在一个与亲免蛋白的TPR结合位点相近但不同的位点与hsp90结合，并且与亲免蛋白一样，p50cdc37被认为参与蛋白激酶的靶向和运输。最近引入的苯醌抗生素格尔德霉素有助于鉴定由基于hsp90的系统陪伴的蛋白质。格尔德霉素与hsp90蛋白家族的成员结合，阻止hsp90异源复合物的组装并使预先形成的异源复合物不稳定。在格尔德霉素存在的情况下，hsp90陪伴的蛋白质的功能被破坏，并且这些蛋白质通过泛素依赖性蛋白酶体机制迅速降解。越来越清楚的是，hsp90陪伴不仅对于多种信号转导途径至关重要，而且对于越来越多的蛋白质的正确折叠、稳定和运输也至关重要。
