Levchenko A, Bruck J, Sternberg P W
Division of Engineering and Applied Science and Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5818-23. doi: 10.1073/pnas.97.11.5818.
In addition to preventing crosstalk among related signaling pathways, scaffold proteins might facilitate signal transduction by preforming multimolecular complexes that can be rapidly activated by incoming signal. In many cases, such as mitogen-activated protein kinase (MAPK) cascades, scaffold proteins are necessary for full activation of a signaling pathway. To date, however, no detailed biochemical model of scaffold action has been suggested. Here we describe a quantitative computer model of MAPK cascade with a generic scaffold protein. Analysis of this model reveals that formation of scaffold-kinase complexes can be used effectively to regulate the specificity, efficiency, and amplitude of signal propagation. In particular, for any generic scaffold there exists a concentration value optimal for signal amplitude. The location of the optimum is determined by the concentrations of the kinases rather than their binding constants and in this way is scaffold independent. This effect and the alteration of threshold properties of the signal propagation at high scaffold concentrations might alter local signaling properties at different subcellular compartments. Different scaffold levels and types might then confer specialized properties to tune evolutionarily conserved signaling modules to specific cellular contexts.
除了防止相关信号通路之间的串扰外，支架蛋白还可能通过预先形成可被传入信号快速激活的多分子复合物来促进信号转导。在许多情况下，如丝裂原活化蛋白激酶（MAPK）级联反应，支架蛋白是信号通路完全激活所必需的。然而，迄今为止，尚未提出支架作用的详细生化模型。在这里，我们描述了一个带有通用支架蛋白的MAPK级联反应的定量计算机模型。对该模型的分析表明，支架 - 激酶复合物的形成可有效地用于调节信号传播的特异性、效率和幅度。特别是，对于任何通用支架，都存在一个对信号幅度最佳的浓度值。最佳位置由激酶的浓度而非其结合常数决定，因此与支架无关。这种效应以及在高支架浓度下信号传播阈值特性的改变可能会改变不同亚细胞区室的局部信号特性。不同的支架水平和类型可能赋予专门的特性，以将进化上保守的信号模块调整到特定的细胞环境。
