Analysing GCN4 translational control in yeast by stochastic chemical kinetics modelling and simulation.
Analysing GCN4 translational control in yeast by stochastic chemical kinetics modelling and simulation.
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DOI：
10.1186/1752-0509-5-131
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发表时间：
2011-08-18
影响因子：
--
通讯作者：
Coghill GM
中科院分区：
文献类型：
--
作者：
You T;Stansfield I;Romano MC;Brown AJ;Coghill GM
酵母通过诱导转录因子Gcn4来应对氨基酸饥饿。这主要是通过依赖于翻译起始的eIF2·GTP·Met-tRNAiMet三元复合物及其5' mRNA先导体的4个上游短开放阅读框（uorf）的翻译控制机制介导的。在正常情况下，这些uorf可减弱GCN4 mRNA的翻译。在氨基酸饥饿期间，三元复合物的水平降低。这通过依赖于uORF间距的扫描/重新启动控制机制克服了GCN4平移衰减效应。利用已发表的实验数据，我们开发并验证了使用化学主方程（模型1）的GCN4翻译的概率公式。模型1解释了GCN4翻译对uORF放置位置的非线性依赖，并预测了在某些条件下调控GCN4翻译的一个尚未确定的因素，只有在反电子间距离异常短时才会对GCN4翻译产生显著影响。不包含该未知因子的更简单的模型2可以很好地代表天然GCN4 mRNA的调控。利用优化后的代数模型2的参数值，我们采用Gillespie算法进行随机模拟，研究不同条件下GCN4 mRNA不同部位核糖体的分布。我们的模拟表明，5'-非翻译区核糖体的装载主要由5'-起始速率和核糖体扫描速率之间的比率决定，而不受三元复合物结合速率的显著影响。重要的是，在抑制和去抑制条件下，缺乏同源trna的密码子的翻译率预计是编码区核糖体装载变化的最重要因素。我们的综合概率模型1和2解释了GCN4的翻译，并有助于阐明一个尚未确定的因素的作用。随后的随机模拟评估了可能影响GCN4 mRNA翻译的不同因素，并将翻译状态与核糖体密度相结合。
The yeast Saccharomyces cerevisiae responds to amino acid starvation by inducing the transcription factor Gcn4. This is mainly mediated via a translational control mechanism dependent upon the translation initiation eIF2·GTP·Met-tRNAiMet ternary complex, and the four short upstream open reading frames (uORFs) in its 5' mRNA leader. These uORFs act to attenuate GCN4 mRNA translation under normal conditions. During amino acid starvation, levels of ternary complex are reduced. This overcomes the GCN4 translation attenuation effect via a scanning/reinitiation control mechanism dependent upon uORF spacing. Using published experimental data, we have developed and validated a probabilistic formulation of GCN4 translation using the Chemical Master Equation (Model 1). Model 1 explains GCN4 translation's nonlinear dependency upon uORF placements, and predicts that an as yet unidentified factor, which was proposed to regulate GCN4 translation under some conditions, only has pronounced effects upon GCN4 translation when intercistronic distances are unnaturally short. A simpler Model 2 that does not include this unidentified factor could well represent the regulation of a natural GCN4 mRNA. Using parameter values optimised for this algebraic Model 2, we performed stochastic simulations by Gillespie algorithm to investigate the distribution of ribosomes in different sections of GCN4 mRNA under distinct conditions. Our simulations demonstrated that ribosomal loading in the 5'-untranslated region is mainly determined by the ratio between the rates of 5'-initiation and ribosome scanning, but was not significantly affected by rate of ternary complex binding. Importantly, the translation rate for codons starved of cognate tRNAs is predicted to be the most significant contributor to the changes in ribosomal loading in the coding region under repressing and derepressing conditions. Our integrated probabilistic Models 1 and 2 explained GCN4 translation and helped to elucidate the role of a yet unidentified factor. The ensuing stochastic simulations evaluated different factors that may impact on the translation of GCN4 mRNA, and integrated translation status with ribosomal density.
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影响因子：
2.6
作者：
You, Tao;Coghill, George M.;Brown, Alistair J. P.
通讯作者：
Brown, Alistair J. P.
影响因子：
3.6
作者：
Berthelot, K;Muldoon, M;McCarthy, JEG
通讯作者：
McCarthy, JEG
影响因子：
10.5
作者：
Asano, K;Clayton, J;Hinnebusch, AG
通讯作者：
Hinnebusch, AG
影响因子：
10.5
作者：
Szamecz, Bela;Rutkai, Edit;Valasek, Leos
通讯作者：
Valasek, Leos
DOI：
10.1109/tsmcc.2004.841906
发表时间：
2005-05-01
期刊：
IEEE TRANSACTIONS ON SYSTEMS MAN AND CYBERNETICS PART C-APPLICATIONS AND REVIEWS
影响因子：
--
作者：
Runarsson, TP;Yao, X
通讯作者：
Yao, X