Many immunoreceptors have cytoplasmic domains that are intrinsically disordered (i.e., have high configurational entropy), have multiple sites of post-translational modification (e.g., tyrosine phosphorylation), and participate in nonlinear signaling pathways (e.g., exhibiting switch-like behavior). Several hypotheses to explain the origin of these nonlinearities fall under the broad hypothesis that modification at one site changes the immunoreceptor's entropy, which in turn changes further modification dynamics. Here we use coarse-grain simulation to study three scenarios, all related to the chains that comprise the T Cell Receptor. We find that, first, if phosphorylation induces local changes in the flexibility of the TCR ζ-chain, this naturally leads to rate enhancements and cooperativity. Second, we find that TCR CD3ε can provide a switch by modulating its residence in the plasma membrane. By constraining our model to be consistent with the previous observation that both basic residues and phosphorylation control membrane residence, we find that there is only a moderate rate enhancement of 10% between first and subsequent phosphorylation events. And third, we find that volume constraints do not limit the number of ZAP70s that can bind the TCR, but that entropic penalties lead to a 200-fold decrease in binding rate by the seventh ZAP70, potentially explaining the observation that each TCR has around six ZAP70 molecules bound following receptor triggering. In all three scenarios, our results demonstrate that phenomena that change an immunoreceptor chain's entropy (stiffening, confinement to a membrane, and multiple simultaneous binding) can lead to nonlinearities (rate enhancement, switching, and negative cooperativity) in how the receptor participates in signaling. These polymer-entropy-driven nonlinearities may augment the nonlinearities that arise from, e.g., kinetic proofreading and cluster formation. They also suggest different design strategies for engineered receptors, e.g., whether or not to put signaling modules on one chain or multiple clustered chains.

中文翻译：

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T细胞受体的内在疾病产生协同作用并控制ZAP70结合

许多免疫受体具有固有地无序的胞质结构域（即，具有高构型熵），具有翻译后修饰的多个位点（例如，酪氨酸磷酸化）并参与非线性信号传导途径（例如，表现出类似开关的行为）。解释这些非线性起源的几种假设属于一个广泛的假设，即一个位点的修饰会改变免疫受体的熵，进而改变进一步的修饰动力学。在这里，我们使用粗粒度模拟来研究三种情况，所有这些情况都与构成T细胞受体的链有关。我们发现，首先，如果磷酸化引起TCRζ链柔性的局部变化，这自然会导致速率增强和协同作用。第二，我们发现TCRCD3ε可以通过调节其在质膜中的驻留来提供开关。通过将我们的模型约束为与先前观察到的基本残基和磷酸化控制膜驻留均一致，我们发现在第一次和随后的磷酸化事件之间仅存在10％的中等速率增强。第三，我们发现体积限制并不限制可以结合TCR的ZAP70的数量，但是熵的惩罚导致第七种ZAP70的结合速率降低200倍，这可能解释了以下观察结果：每个TCR大约有六个ZAP70分子在受体触发后结合。在所有这三种情况下，我们的结果表明，这些现象会改变免疫受体链的熵（变硬，局限于膜，以及多个同时绑定）会导致受体参与信号传递方式的非线性（速率增强，切换和负协作性）。这些由聚合物熵驱动的非线性可能会增加由例如动力学校对和簇形成引起的非线性。他们还提出了针对工程受体的不同设计策略，例如，是否将信号模块置于一条链或多条簇链上。