Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
Adv Exp Med Biol. 2018;1106:73-83. doi: 10.1007/978-3-030-00737-9_5.
Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin-like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3-kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co-cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works.
细胞稳定性、大分子复合物的组装和激活需要 HSP90 与 R2TP/Prefoldin 样（R2TP/PFDL）共伴侣协同作用。RNA 聚合酶 II、snoRNPs 和 PI3-激酶样激酶复合物，包括 ATM、ATR、DNA-PKcs、TRAPP、SMG1 和 mTOR 蛋白，都是 HSP90-R2TP 系统的客户。有证据表明 R2TP/PFDL 途径与癌症有关，很可能是因为它在癌症中经常失调的途径中起着至关重要的作用。R2TP 构成共伴侣的核心，并协调 HSP90 和客户的招募，而 Prefoldin 和其他 Prefoldin 样蛋白，包括 URI，与 R2TP 相关联，但它们的功能仍不清楚。R2TP/PFLD 促进如此多种大分子复合物组装和激活的机制尚未完全了解。最近在 R2TP 的结构特征描述方面的努力已经开始提供一些机制上的见解。我们总结了最近的结构发现，特别是低温电子显微镜（cryo-EM）如何帮助我们理解 R2TP 核心复合物的结构。在酵母和人类 R2TP 之间发现的结构差异揭示了后生动物 R2TP 复合物的出乎意料的复杂性，并提出了关于 R2TP/PFLD 如何工作的新的有趣问题。
