Split Histidine Kinases Enable Ultrasensitivity and Bistability in Two-Component Signaling Networks

Bacteria sense and respond to their environment through signaling cascades generally referred to as two-component signaling networks. These networks comprise histidine kinases and their cognate response regulators. Histidine kinases have a number of biochemical activities: ATP binding, autophosphorylation, the ability to act as a phosphodonor for their response regulators, and in many cases the ability to catalyze the hydrolytic dephosphorylation of their response regulator. Here, we explore the functional role of “split kinases” where the ATP binding and phosphotransfer activities of a conventional histidine kinase are split onto two distinct proteins that form a complex. We find that this unusual configuration can enable ultrasensitivity and bistability in the signal-response relationship of the resulting system. These dynamics are displayed under a wide parameter range but only when specific biochemical requirements are met. We experimentally show that one of these requirements, namely segregation of the phosphatase activity predominantly onto the free form of one of the proteins making up the split kinase, is met in Rhodobacter sphaeroides. These findings indicate split kinases as a bacterial alternative for enabling ultrasensitivity and bistability in signaling networks. Genomic analyses reveal that up 1.7% of all identified histidine kinases have the potential to be split and bifunctional.

细菌可通过通常被称为双组分信号网络（two-component signaling networks）的信号级联反应感知并响应周遭环境。这类网络由组氨酸激酶（histidine kinases）及其同源响应调控因子构成。组氨酸激酶具备多项生化活性：ATP结合、自身磷酸化、作为其同源响应调控因子的磷酸供体，且在多数情况下还可催化响应调控因子的水解去磷酸化过程。本研究针对“分裂型激酶”（split kinases）的功能角色展开探讨——这类激酶将常规组氨酸激酶的ATP结合与磷酸转移活性拆分至两个形成复合物的不同蛋白质上。我们发现，这种特殊的结构可使所得系统的信号-响应关系呈现超敏性（ultrasensitivity）与双稳态（bistability）。这类动力学行为可在宽泛的参数范围内被观测到，但仅当满足特定生化条件时才会发生。我们通过实验证实，其中一项必要条件——即磷酸酶活性主要富集于组成分裂型激酶的其中一种蛋白质的游离形式——在球形红杆菌（Rhodobacter sphaeroides）中得以满足。上述研究结果表明，分裂型激酶是细菌实现信号网络中超敏性与双稳态的一种备选机制。基因组分析显示，在所有已鉴定的组氨酸激酶中，最高可达1.7%的激酶具备成为分裂型双功能激酶的潜力。