THE OR CONTROL-SYSTEM OF BACTERIOPHAGE-LAMBDA - A PHYSICAL-CHEMICAL MODEL FOR GENE-REGULATION
THE OR CONTROL-SYSTEM OF BACTERIOPHAGE-LAMBDA - A PHYSICAL-CHEMICAL MODEL FOR GENE-REGULATION
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DOI：
10.1016/0022-2836(85)90086-5
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发表时间：
1985-01-01
影响因子：
5.6
通讯作者：
ACKERS, GK
中科院分区：
文献类型：
--
作者：
SHEA, MA;ACKERS, GK
建立了噬菌体Lambda过程的定量模型。控制着从溶源模式到溶源模式的转换生长。这些过程包括Ci抑制子和cro蛋白在右操纵子的3个DNA位点的相互作用，RNA聚合酶与启动子PR和Prm的结合，Ci抑制子和cro蛋白的合成，以及recA在诱导裂解过程中的降解作用。该模型由两个主要的物理化学部分组成：一个是控制系统各种分子构型的相对概率的统计热力学理论；另一个是这些概率与功能事件(包括调节蛋白Ci和cro的合成)耦合的动力学模型。使用独立评估的相互作用常数和速率参数，发现该模型能够预测系统在较长时间内的基本生理特征。该模型足以预测已知的生理特性，这为其构建中使用的物理化学假设提供了证据。通过模型规定的分子相互作用的非线性、时间依赖、反馈调制的组合，发现几个主要的生理特征作为系统属性出现。这些包括：在没有recA介导的Ci抑制物降解的情况下维持溶源状态；诱导裂解和亚诱导现象；以及自身负调控CRO。该模型被用来确定几个关键的分子过程在复合系统中的作用，这些过程以前是通过体外研究来描述的。这些包括：Ci抑制物与DNA结合的协作性；抑制物与RNA聚合酶之间的相互作用(阳性对照)；以及Ci抑制物分子的单体-二聚体结合。Ci抑制物协同作用的一个主要作用是确保细胞内Ci抑制物水平轻微变化时溶原性状态的稳定性。积极对照的作用似乎是提供峰值的，而不是单调的，依赖于Ci抑制物水平的PRM活性，同时允许PR活性是一个阶梯函数。该模型关联了大量的体内和体外研究，并对噬菌体lambda的分子现象和生理特征做出了可检验的预测。这项研究中开发的方法可以扩展到包括.lambda的更多功能。系统和治疗其他系统的基因调控。
A quantitativee model was developed for processes in the bacteriophage .lambda. that control the switchover from lysogenic to lytic modes growth. These processes include the interactions of cI repressor and cro proteins at the 3 DNA sites of the right operator, OR, the binding of RNA polymerase at promoters PR and PRM, the synthesis of cI repressor and cro proteins, and the degradative action of recA during induction of lysis. The model is comprised of 2 major physical-chemical components: a statistical thermodynamic theory for relative probabilities of the various molecular configurations of the control system; and a kinetic model for coupling of these probabilities to functional events, including synthesis of regulatory proteins cI and cro. Using independently evaluated interaction constants and rate parameters, the model was found capable of predicting essential physiological characteristics of the system over an extended time. Sufficiency of the model to predict known physiological properties lends credence to the physical-chemical assumptions used in its construction. Several major physiological characteristics were found to arise as system properties through the non-linear, time-dependent, feedback-modulated combinations of molecular interactions prescribed by the model. These include: maintenance of the lysogenic state in the absence of recA-mediated cI repressor degradation; induction of lysis and the phenonmenon of subinduction; and autogeneous negative control of cro. The model was used to determine the roles, within the composite system, of several key molecular processes previously characterized by studies in vitro. These include: cooperativity in cI repressor binding to DNA; interactions between repressors and RNA polymerase (positive control); and the monomer-dimer association of cI repressor molecules. A major role of cI repressor cooperativity is that of guaranteeing stability of the lysogenic state against minor changes in cI repressor levels within the cell. The role of positive control seems to be that of providing for a peaked, rather than monotonic, dependence of PRM activity on cI repressor level, while permitting PR activity to be a step function. The model correlates an immense body of studies in vivo and in vitro, and it makes testable predictions about molecular phenomena as well as physiological characteristics of bacteriophage .lambda.. The approach developed in this study can be extended to include more features of the .lambda. system and to treat other systems of gene regulation.