RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.
RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.
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DOI：
10.1038/s41467-018-03942-1
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发表时间：
2018-04-16
影响因子：
16.6
通讯作者：
Llorca O
中科院分区：
文献类型：
--
作者：
Martino F;Pal M;Muñoz-Hernández H;Rodríguez CF;Núñez-Ramírez R;Gil-Carton D;Degliesposti G;Skehel JM;Roe SM;Prodromou C;Pearl LH;Llorca O
R2TP/Prefoldin样共伴侣与HSP90结合，促进RNA聚合酶II和PI3-激酶样激酶复合体(如mTOR)的组装和细胞稳定性。然而，人们对这种情况发生的机制知之甚少。在这里，我们使用冷冻EM和对人类R2TP核心(RUVBL1-RUVBL2-RPAP3-PIH1D1)的研究，揭示了RPAP3的独特作用，将后生动物R2TP与较小的酵母等同物区分开来。RPAP3跨越单个RUVBL环的两个面，提供了一个扩展的脚手架，可以招募客户，并为HSP90提供了灵活的系绳。3.6RPAP3的C-末端结构域与RUVBL2的ATPase结构域直接相互作用，这是人类R2TP组装所必需的，但在酵母中不存在。3.6RPARYO-EM结构揭示了RPAP3的C-末端结构域与RUVBL2的ATPase结构域的直接相互作用，这是人类R2TP组装所必需的，但在酵母中不存在。 äcryo-EM结构揭示了RPAP3的C末端结构域与RUVBL2的ATPase结构域的直接相互作用。RPAP3的移动TPR结构域映射到环的对面，与PIH1D1结合，介导客户蛋白募集。因此，RPAP3为HSP90与各种客户蛋白的接近提供了一个灵活的平台。R2TP/PFDL共伴侣通过一种迄今未知的机制促进RNA聚合酶II和PI3-激酶样激酶的组装，如mTOR。在这里，作者提供了人类R2TP的冷冻EM结构，这表明RPAP3是如何作为一个灵活的平台将HSP90招募到不同的客户蛋白。
The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this occurs is poorly understood. Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1–RUVBL2–RPAP3–PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. A 3.6 Å cryo-EM structure reveals direct interaction of a C-terminal domain of RPAP3 and the ATPase domain of RUVBL2, necessary for human R2TP assembly but absent from yeast. The mobile TPR domains of RPAP3 map to the opposite face of the ring, associating with PIH1D1, which mediates client protein recruitment. Thus, RPAP3 provides a flexible platform for bringing HSP90 into proximity with diverse client proteins. The R2TP/PFDL co-chaperone facilitates assembly of RNA polymerase II and PI3-kinase-like kinases such as mTOR by a so far unknown mechanism. Here authors provide the cryo-EM structure of human R2TP, which shows how RPAP3 serves as a flexible platform to recruit HSP90 to diverse client proteins.
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影响因子：
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作者：
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通讯作者：
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