Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis
Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis
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DOI：
10.1093/jn/136.1.227s
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发表时间：
2006-01-01
影响因子：
4.2
通讯作者：
Jefferson, LS
中科院分区：
文献类型：
--
作者：
Kimball, SR;Jefferson, LS
支链氨基酸可促进骨骼肌体外制剂中蛋白质的合成。同样，摄入混合膳食对骨骼肌蛋白质合成的刺激在很大程度上是由于支链氨基酸。在三种支链氨基酸中，亮氨酸主要负责在这些情况下刺激蛋白质合成。亮氨酸对蛋白质合成的刺激作用是通过上调信使核糖核酸翻译的启动来实现的。许多机制，包括核糖体蛋白S6Kinase的磷酸化，真核细胞启动因子(ELF)4E结合蛋白-1，以及elF4G，有助于亮氨酸对翻译起始的影响。这些机制不仅促进了信使核糖核酸的全球翻译，而且在选择要翻译的信使核糖核酸的过程中起到了中介作用。控制这些磷酸化诱导机制的信号通路中的一个关键成分是蛋白激酶，被称为雷帕霉素的哺乳动物靶点(MTOR)。MTOR针对下游靶点的活性部分是通过它与mTOR调控相关蛋白(称为Raptor)和G蛋白β亚基样蛋白的相互作用来控制的。通过mTOR的信号也由该途径的上游成员控制，例如大脑中富含的RAS同系物(Rheb)，一种激活mTOR的GTPase，以及tuberin(也称为TSC2)，一种GTPase激活蛋白，与其结合伙伴hamartin(也称为TSC1)一起抑制mTOR。通过mTOR途径调节亮氨酸刺激信号的候选分子包括TSC2、Rheb和Raptor。本文就亮氨酸如何作用于这些信号通路和刺激骨骼肌蛋白质合成的分子机制的研究现状作一综述。
BCAAs stimulate protein synthesis in in vitro preparations of skeletal muscle. Likewise, the stimulation of protein synthesis in skeletal muscle produced by intake of a mixed meal is due largely to BCAAs. Of the three BCAAs, leucine is the one primarily responsible for the stimulation of protein synthesis under these circumstances. The stimulatory effect of leucine on protein synthesis is mediated through upregulation of the initiation of mRNA translation. A number of mechanisms, including phosphorylation of ribosomal protein S6 Kinase, eukaryotic initiation factor (elF)4E binding protein-1, and elF4G, contribute to the effect of leucine on translation initiation. These mechanisms not only promote global translation of mRNA but also contribute to processes that mediate discrimination in the selection of mRNA for translation. A key component in a signaling pathway controlling these phosphorylation-induced mechanisms is the protein kinase, termed the mammalian target of rapamycin (mTOR). The activity of mTOR toward downstream targets is controlled in part through its interaction with the regulatory-associated protein of mTOR (known as raptor) and the G protein beta-subunit-like protein. Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain (Rheb), a GTPase that activates mTOR, and tuberin (also known as TSC2), a GTPase-activating protein, which, with its binding partner hamartin (also known as TSC1), acts to repress mTOR. Candidates for mediating the action of leucine to stimulate signaling through the mTOR pathway include TSC2, Rheb, and raptor. The current state of our understanding of how leucine acts on these signaling pathways and molecular mechanisms to stimulate protein synthesis in skeletal muscle is summarized in this article.