Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):2930-2937. doi: 10.1073/pnas.1912745117. Epub 2020 Jan 24.
Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities-the catalytic potential Q-in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.
支架蛋白通过将信号分子相互作用来组织细胞过程，有时通过形成大的信号体。已知有几种支架可以聚合。因此，它们的组装不应被理解为化学计量的聚集体，而应被理解为组合集合。我们分析了在连续体和离散体设置中加载在聚合支架上的配体的组合相互作用，并将其与具有固定结合位点数量的多价支架进行了比较。感兴趣的数量是配体相互作用可能性的丰富度 - 催化潜力 Q - 在构象混合物中的丰富度。随着支架丰度的增加，已知支架系统首先增加了配体相互作用的机会，然后随着配体在不同的支架上变得孤立，关闭了这些机会。聚合系统的突出之处在于，Q 对单体浓度的依赖性从由一级项主导切换到由聚合亲和力确定的范围内的二级项主导。这种行为使 Q 超过了任何多价支架系统的 Q。此外，随后的下降幅度大大减轻，因为 Q 随单体浓度的下降幅度比任何多价支架都要小一半。我们根据聚合物长度分布的浓度曲线如何适应单体浓度和亲和力的变化来解释这种行为。离散情况结果类似，但由于最大聚合物尺寸，在单体数量较小时，行为可能会被夸大，类似于晶格上键渗流的有限大小效应。
