Redesigning TOR Kinase to Explore the Structural Basis for TORC1 and TORC2 Assembly.
Redesigning TOR Kinase to Explore the Structural Basis for TORC1 and TORC2 Assembly.
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DOI：
10.3390/biom8020036
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发表时间：
2018-06-01
期刊：
影响因子：
5.5
通讯作者：
Powers T
中科院分区：
文献类型：
--
作者：
Hill A;Niles B;Cuyegkeng A;Powers T
TOR是一种丝氨酸/苏氨酸蛋白激酶，其组装成不同的TOR复合物1和2（TORC 1或TORC 2）以调节细胞生长。在哺乳动物细胞中，单个mTOR稳定地并入mTORC 1和mTORC 2中。相比之下，在酿酒酵母中，存在两种高度相似的Tor 1和Tor 2蛋白，其中Tor 1专门组装成TORC 1，Tor 2优先组装成TORC 2。为了深入了解TOR复合物组装，我们在酵母中使用这种分叉来识别Tor 1和Tor 2中控制其复合物特异性的结构元件。我们已经确定了一个简洁的区域内的N-末端的Tor 2，我们称之为主要组装特异性（MAS）域，这是足以赋予显着的TORC 2活性时，放置到一个其他的Tor 1蛋白。一致地，将来自Tor 1的相应MAS结构域引入另外的Tor 2足以赋予与TORC 1特异性组分的稳定缔合。值得注意的是，与mTOR非常相似，后一种嵌合体也保留了与TORC 2组分的稳定相互作用，表明整个Tor 1/Tor 2的决定簇有助于复杂的特异性。我们的研究结果是在最近的超微结构研究的TORC 1和TORC 2，MAS域参与了重要的复合物的形成和/或稳定性的季相互作用非常一致。
TOR is a serine/threonine protein kinase that assembles into distinct TOR Complexes 1 and 2 (TORC1 or TORC2) to regulate cell growth. In mammalian cells, a single mTOR incorporates stably into mTORC1 and mTORC2. By contrast, in Saccharomyces cerevisiae, two highly similar Tor1 and Tor2 proteins exist, where Tor1 assembles exclusively into TORC1 and Tor2 assembles preferentially into TORC2. To gain insight into TOR complex assembly, we used this bifurcation in yeast to identify structural elements within Tor1 and Tor2 that govern their complex specificity. We have identified a concise region of ~500 amino acids within the N-terminus of Tor2, which we term the Major Assembly Specificity (MAS) domain, that is sufficient to confer significant TORC2 activity when placed into an otherwise Tor1 protein. Consistently, introduction of the corresponding MAS domain from Tor1 into an otherwise Tor2 is sufficient to confer stable association with TORC1-specific components. Remarkably, much like mTOR, this latter chimera also retains stable interactions with TORC2 components, indicating that determinants throughout Tor1/Tor2 contribute to complex specificity. Our findings are in excellent agreement with recent ultrastructural studies of TORC1 and TORC2, where the MAS domain is involved in quaternary interactions important for complex formation and/or stability.
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