支架介导的蛋白质信号复合物成核的基本原理
Scaffold-mediated Nucleation of Protein Signaling Complexes: Elementary Principles
摘要：
具有多个结合位点的蛋白质通过使蛋白质复合物成核而在细胞信号转导系统中发挥重要作用，其中，例如，酶和底物是共定位的。专门负责这一功能的蛋白质有各种各样的名称，包括衔接子、连接子和支架。支架介导的蛋白质复合物成核可以是组成型的或诱导型的。诱导成核通常由磷酸化激活的支架上的停靠位点介导。在这里，通过考虑最低限度的数学模型，它概括了在更详细的机械模型中看到的支架效应，我们获得了分析和数值结果，提供了对支架功能的见解。这些结果阐明了如何招聘的一对配体的支架上依赖于配体的浓度，对配体-支架相互作用的结合常数，结合协同性，并对环境的支架，配体招聘的竞争性配体和诱饵受体的影响。对于二价支架的情况，我们获得了最大限度地招募一对单价配体的独特支架浓度的表达式。通过模拟，我们证明了当支架以不同浓度存在时，二价支架可以使不同的配体组成核到等同的程度。因此，支架的功能可能随着拷贝数的变化而发生质的变化。我们还展示了支架如何改变酶的催化效率和反应速率对底物浓度的敏感性。这里提出的结果应该是有用的理解支架功能和工程支架具有所需的性能。
英文摘要：
Proteins with multiple binding sites play important roles in cell signaling systems by nucleating protein complexes in which, for example, enzymes and substrates are co-localized. Proteins that specialize in this function are called by a variety names, including adapter, linker and scaffold. Scaffold-mediated nucleation of protein complexes can be either constitutive or induced. Induced nucleation is commonly mediated by a docking site on a scaffold that is activated by phosphorylation. Here, by considering minimalist mathematical models, which recapitulate scaffold effects seen in more mechanistically detailed models, we obtain analytical and numerical results that provide insights into scaffold function. These results elucidate how recruitment of a pair of ligands to a scaffold depends on the concentrations of the ligands, on the binding constants for ligand-scaffold interactions, on binding cooperativity, and on the milieu of the scaffold, as ligand recruitment is affected by competitive ligands and decoy receptors. For the case of a bivalent scaffold, we obtain an expression for the unique scaffold concentration that maximally recruits a pair of monovalent ligands. Through simulations, we demonstrate that a bivalent scaffold can nucleate distinct sets of ligands to equivalent extents when the scaffold is present at different concentrations. Thus, the function of a scaffold can potentially change qualitatively with a change in copy number. We also demonstrate how a scaffold can change the catalytic efficiency of an enzyme and the sensitivity of the rate of reaction to substrate concentration. The results presented here should be useful for understanding scaffold function and for engineering scaffolds to have desired properties.
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