The Hsp90 cochaperone TTT promotes cotranslational maturation of PIKKs prior to complex assembly
The Hsp90 cochaperone TTT promotes cotranslational maturation of PIKKs prior to complex assembly
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DOI：
10.1016/j.celrep.2021.109867
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发表时间：
2021-10-19
期刊：
影响因子：
8.8
通讯作者：
Helmlinger, Dominique
中科院分区：
文献类型：
--
作者：
Toullec, Damien;Elias-Villalobos, Alberto;Helmlinger, Dominique
磷脂酰肌醇3-激酶相关激酶（PIKK）是控制基本过程（包括细胞生长、DNA损伤修复和基因表达）的激酶家族。尽管它们的调节和活性被很好地表征，但对PIKK如何折叠和组装成活性复合物知之甚少。以前的工作已经确定了热休克蛋白90（Hsp 90）cochaperone，TTT复合物，特异性稳定PIKKs。在这里，我们描述了一种机制，TTT促进他们的从头成熟裂变酵母。我们发现，TTT识别新合成的PIKKs在翻译过程中。虽然PIKKs形成多聚体复合物，我们发现，他们不从事共翻译组装与他们的合作伙伴。相反，我们的研究结果表明，TTT保护新生PIKK多肽免于错误折叠和降解的模型，因为PIKK在翻译终止后获得其天然状态。因此，PIKK成熟和组装是暂时分离的，这表明大复合物的生物发生需要专用的分子伴侣和亚基之间的共翻译相互作用。
Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of kinases that control fundamental processes, including cell growth, DNA damage repair, and gene expression. Although their regulation and activities are well characterized, little is known about how PIKKs fold and assemble into active complexes. Previous work has identified a heat shock protein 90 (Hsp90) cochaperone, the TTT complex, that specifically stabilizes PIKKs. Here, we describe a mechanism by which TTT promotes their de novo maturation in fission yeast. We show that TTT recognizes newly synthesized PIKKs during translation. Although PIKKs form multimeric complexes, we find that they do not engage in cotranslational assembly with their partners. Rather, our findings suggest a model by which TTT protects nascent PIKK polypeptides from misfolding and degradation because PIKKs acquire their native state after translation is terminated. Thus, PIKK maturation and assembly are temporally segregated, suggesting that the biogenesis of large complexes requires both dedicated chaperones and cotranslational interactions between subunits.