Protein synthesis regulation primarily occurs at translation initiation, the first step of gene translation. However, the regulation of translation initiation under various conditions is not fully understood. Specifically, the reason why protein production from certain mRNAs remains resistant to stress while others do not show such resilience. Moreover, why is protein production enhanced from a few transcripts under stress conditions, whereas it is decreased in the majority of transcripts? We address them by developing a Monte Carlo simulation model of protein synthesis and ribosome scanning. We find that mRNAs with strong Kozak contexts exhibit minimal reduction in translation initiation rate under stress conditions. Moreover, these transcripts exhibit even greater resilience to stress when the scanning speed of 43S ribosome subunit is slow, albeit at the cost of reduced initiation rate. This implies a trade-off between initiation rate and the ability of mRNA to withstand stress. We also show that mRNAs featuring an upstream ORF can act as a regulatory switch. This switch elevates protein production from the main ORF under stress conditions; however, minimal to no proteins are produced under the normal condition. Because, in stress, a larger fraction of 43S ribosomes bypasses the upstream ORF due to its weak Kozak context. This, in turn, increases the number of scanning ribosomes reaching the main ORF, whose strong Kozak context can convert them into 80S ribosomes, even under stress conditions. This switching allows an efficient use of cellular resources by producing proteins when they are required. Thus, our computational study provides valuable insights into our understanding of stress-responsive translation-initiation.

中文翻译：

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了解应激条件下蛋白质合成的调控


蛋白质合成调控主要发生在翻译起始阶段，这是基因翻译的第一步。然而，在各种条件下翻译起始的调节尚不完全清楚。具体来说，为什么某些 mRNA 产生的蛋白质仍然对压力有抵抗力，而另一些 mRNA 则没有表现出这种弹性。此外，为什么在应激条件下，少数转录本的蛋白质产生增加，而大多数转录本的蛋白质产生减少？我们通过开发蛋白质合成和核糖体扫描的 Monte Carlo 模拟模型来解决这些问题。我们发现，在应激条件下，具有强 Kozak 背景的 mRNA 的翻译起始速率降低最小。此外，当 43S 核糖体亚基的扫描速度较慢时，这些转录本对压力表现出更大的弹性，尽管代价是起始速率降低。这意味着起始速率和 mRNA 承受压力的能力之间的权衡。我们还表明，具有上游 ORF 的 mRNA 可以充当调节开关。在应激条件下，这种开关提高了主 ORF 的蛋白质产量;然而，在正常条件下，产生很少或没有蛋白质。因为，在应激下，由于较弱的 Kozak 环境，很大一部分 43S 核糖体绕过了上游 ORF。反过来，这增加了到达主 ORF 的扫描核糖体的数量，即使在应激条件下，其强大的 Kozak 环境也可以将它们转化为 80S 核糖体。这种转换允许在需要时产生蛋白质来有效利用细胞资源。因此，我们的计算研究为我们理解压力响应翻译起始提供了有价值的见解。