Structural Conservation of Components in the Amino Acid Sensing Branch of the TOR Pathway in Yeast and Mammals
Structural Conservation of Components in the Amino Acid Sensing Branch of the TOR Pathway in Yeast and Mammals
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DOI：
10.1016/j.jmb.2010.07.034
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发表时间：
2010-09-17
影响因子：
5.6
通讯作者：
Fass, Deborah
中科院分区：
文献类型：
--
作者：
Kogan, Konstantin;Spear, Eric D.;Fass, Deborah
高度保守的Rag家族GTP酶在向TOR（雷帕霉素靶蛋白）信号复合物报告氨基酸可用性方面发挥作用，该复合物根据环境信号调节细胞生长和代谢。多项独立研究表明，酵母Rag蛋白Gtr1p和Gtr2p与膜相关蛋白Gse1p（Ego3p）和Gse2p（Ego1p）相互作用。然而，无法鉴定出Gse1p和Gse2p的哺乳动物同源物。我们测定了Gse1p的晶体结构，发现它与两种哺乳动物蛋白MP1（丝裂原活化蛋白激酶支架蛋白1）和p14的折叠结构相匹配，这两种蛋白形成异二聚体复合物，该复合物在丝裂原活化蛋白激酶途径中被赋予支架功能。这种结构相似性的重要性通过最近鉴定出哺乳动物Rag蛋白与MP1/p14之间的物理和功能关联而得到验证。总之，这些发现表明，尽管序列在一定程度上发生分化，以至于通过简单的同源性搜索无法检测到，但TOR信号通路的关键成分在酵母和哺乳动物之间在结构上是保守的。（C）2010爱思唯尔有限公司。保留所有权利。
The highly conserved Rag family GTPases have a role in reporting amino acid availability to the TOR (target of rapamycin) signaling complex, which regulates cell growth and metabolism in response to environmental cues. The yeast Rag proteins Gtr1p and Gtr2p were shown in multiple independent studies to interact with the membrane-associated proteins Gse1p (Ego3p) and Gse2p (Ego1p). However, mammalian orthologs of Gse1p and Gse2p could not be identified. We determined the crystal structure of Gse1p and found it to match the fold of two mammalian proteins, MP1 (mitogen-activated protein kinase scaffold protein 1) and p14, which form a heterodimeric complex that had been assigned a scaffolding function in mitogen-activated protein kinase pathways. The significance of this structural similarity is validated by the recent identification of a physical and functional association between mammalian Rag proteins and MP1/p14. Together, these findings reveal that key components of the TOR signaling pathway are structurally conserved between yeast and mammals, despite divergence of sequence to a degree that thwarts detection through simple homology searches. (C) 2010 Elsevier Ltd. All rights reserved.