Department of Physics, University of Toronto, 60 St George St, Toronto, ON M5S 1A7, Canada.
Institute for Biomedical Engineering, University of Toronto, 164 college St, Toronto, ON M5S 1A7, Canada.
Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2212795120. doi: 10.1073/pnas.2212795120. Epub 2023 May 16.
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.
动力学校读（KPR）已被用作细胞受体对配体高特异性进行解释的范例。KPR 增强了不同配体相对于非校读受体的平均受体占有率之间的差异，从而可能实现更好的区分。另一方面，校读相对于非校读受体也会减弱信号，并引入额外的随机受体转换。这增加了下游信号中噪声的相对幅度，从而可能干扰可靠的配体区分。为了理解除了比较平均信号之外噪声对配体区分的影响，我们将配体区分的任务表述为基于分子信号输出对配体受体亲和力进行统计估计的问题。我们的分析表明，与非校读受体相比，校读通常会使配体的分辨率恶化。此外，在大多数通常被认为是生物学上的条件下，随着校读步骤的增加，分辨率进一步下降。这与 KPR 通过额外的校读步骤普遍改善配体区分的通常观点形成对比。我们的结果在各种不同的校读方案和性能指标上是一致的，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所特有的。基于我们的结果，我们建议 KPR 方案在多配体/多输出途径中具有替代作用，例如复用和组合编码。
