PDF(Pubmed)
Abstract：
Certain proteins assemble into diverse complex states, each having a distinct and unique function in the cell. Target of rapamycin (Tor) complex 1 (TORC1) plays a central role in signalling pathways that allow cells to respond to the environment, including nutritional status signalling. TORC1 is widely recognised for its association with various diseases. The budding yeast Saccharomyces cerevisiae has two types of TORC1, Tor1-containing TORC1 and Tor2-containing TORC1, which comprise different constituent proteins but are considered to have the same function. Here, we computationally modelled the relevant complex structures and then, based on the structures, rationally engineered a Tor2 mutant that could form Tor complex 2 (TORC2) but not TORC1, resulting in a redesign of the complex states. Functional analysis of the Tor2 mutant revealed that the two types of TORC1 induce different phenotypes, with changes observed in rapamycin, caffeine and pH dependencies of cell growth, as well as in replicative and chronological lifespan. These findings uncovered by a general approach with huge potential - model structure-based engineering - are expected to provide further insights into various fields such as molecular evolution and lifespan.
摘要：
某些蛋白质组装成不同的复杂状态，每个在细胞中都有独特的功能。雷帕霉素靶蛋白（Tor）复合物1（TORC1）在信号通路中起着核心作用，使细胞对环境做出反应。包括营养状况信号。TORC1因其与各种疾病的关联而被广泛认可。出芽酵母酿酒酵母具有两种类型的TORC1,含Tor1的TORC1和含Tor2的TORC1,它们包含不同的组成蛋白,但被认为具有相同的功能。这里,我们对相关的复杂结构进行了计算建模，基于结构，合理地设计了可以形成Tor复合物2（TORC2）而不是TORC1的Tor2突变体，从而重新设计了复杂状态。Tor2突变体的功能分析显示两种类型的TORC1诱导不同的表型,观察到雷帕霉素的变化，咖啡因和细胞生长的pH依赖性，以及复制和按时间顺序排列的寿命。这些发现由具有巨大潜力的通用方法-基于模型结构的工程-有望为分子进化和寿命等各个领域提供进一步的见解。
