Proofreading does not result in more reliable ligand discrimination in receptor signaling due to its inherent stochasticity.
Proofreading does not result in more reliable ligand discrimination in receptor signaling due to its inherent stochasticity.
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DOI：
10.1073/pnas.2212795120
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发表时间：
2023-05-23
影响因子：
11.1
通讯作者：
Zilman, Anton
中科院分区：
文献类型：
--
作者：
Kirby, Duncan;Zilman, Anton
细胞信号传导要求细胞可靠地区分不同类型的分子，以传达有关细胞环境的信息。动力学校对（KPR）模型是用于解释细胞高精度分子辨别观察结果的主要范式之一。然而，在量化这些系统中的辨别性能时，通常不考虑分子噪声的影响。我们表明，当考虑到噪声时，KPR 通常不会改善相对于非校对受体的信号辨别能力，并且会显着降低性能。我们比较了多个 KPR 模型，结果表明受体活性差异的增加是校对机制本身固有的。结果提出了关于噪声在分子信号传导精度中的作用的问题。动力学校对（KPR）已被用作细胞受体配体辨别的高度特异性的范例解释。与未经校对的受体相比，KPR 增强了不同配体之间平均受体占据率的差异，从而有可能实现更好的区分。另一方面，校对也会减弱信号，并相对于非校对受体引入额外的随机受体转变。这增加了下游信号中噪声的相对幅度，这可能会干扰可靠的配体辨别。为了了解噪声对平均信号比较之外的配体辨别的影响，我们将配体辨别任务制定为基于分子信号输出的配体受体亲和力的统计估计问题。我们的分析表明，与未经校对的受体相比，校对通常会恶化配体分辨率。此外，在最常见的生物学条件下，随着校对步骤的增多，分辨率进一步降低。这与通常的观念形成鲜明对比，即 KPR 通过额外的校对步骤普遍提高了配体辨别能力。我们的结果在各种不同的校对方案和性能指标中都是一致的，这表明它们是 KPR 机制本身固有的，而不是任何特定的分子噪声模型。根据我们的结果，我们建议 KPR 方案发挥替代作用，例如多配体/多输出途径中的复用和组合编码。
Cellular signaling requires cells to reliably discriminate between different types of molecules to convey information about the cell environment. The kinetic proofreading (KPR) model is one of the main paradigms used to explain observations of highly precise molecular discrimination by cells. However, the effect of molecular noise is typically not accounted for when quantifying discrimination performance in these systems. We show that when noise is accounted for, KPR generally does not improve signal discrimination relative to a nonproofreading receptor and can substantially degrade the performance. We compare multiple KPR models to show that increased variance in receptor activity is intrinsic to the proofreading mechanism itself. The results raise questions about the role of noise in the precision of molecular signaling. Kinetic proofreading (KPR) has been used as a paradigmatic explanation for the high specificity of ligand discrimination by cellular receptors. KPR enhances the difference in the mean receptor occupancy between different ligands compared to a nonproofread receptor, thus potentially enabling better discrimination. On the other hand, proofreading also attenuates the signal and introduces additional stochastic receptor transitions relative to a nonproofreading receptor. This increases the relative magnitude of noise in the downstream signal, which can interfere with reliable ligand discrimination. To understand the effect of noise on ligand discrimination beyond the comparison of the mean signals, we formulate the task of ligand discrimination as a problem of statistical estimation of the receptor affinity of ligands based on the molecular signaling output. Our analysis reveals that proofreading typically worsens ligand resolution compared to a nonproofread receptor. Furthermore, the resolution decreases further with more proofreading steps under most commonly biologically considered conditions. This contrasts with the usual notion that KPR universally improves ligand discrimination with additional proofreading steps. Our results are consistent across a variety of different proofreading schemes and metrics of performance, suggesting that they are inherent to the KPR mechanism itself rather than any particular model of molecular noise. Based on our results, we suggest alternative roles for KPR schemes such as multiplexing and combinatorial encoding in multi-ligand/multi-output pathways.
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