Two Component Signal Transduction Networks in Myxococcus xanthus

职务名称：黄色粘球菌中的双组分信号转导网络智力优势：黄色粘球菌是分化、细胞间通讯、表面运动和生物复杂性的细菌模型。它整合了来自环境的复杂刺激，以调节决策过程，最终形成抗逆孢子。信号系统的一个关键类别由“两个组件”（传感器和调节器）组成，它们直接将环境刺激与行为和基因表达的控制联系起来。通常，传感器和调节器由染色体上彼此相邻的基因编码，因此预测其包含特定的“双组分系统”（TCS）以调节细胞的生物学。黄色分枝杆菌编码至少144个传感器组氨酸激酶（HK）和150个反应调节因子（RR）蛋白，其中许多蛋白似乎是随机定位在染色体上。因此，黄色分枝杆菌拥有细菌世界中最复杂和最大的信号转导能力库之一。由于这些进化上相关的双组分蛋白质之间的显著相似性，防止不期望的“串扰”（异常信号传导或错误通信），同时还管理系统之间的真正交叉调节是调节黄曲霉群落结构的关键特征。为了探索TCS保持特异性或赋予交叉调节的特征，拟议的研究将集中在M.通过它们在染色体上的基因簇内的存在来描绘xanthus。先前的工作表明，在M.xanthus中，两个这样的系统之间存在复杂的相互作用，影响孢子的形成。对这些通路的进一步剖析导致发现传感器HK既作为激酶又作为磷酸酶朝向其靶调节剂发挥作用。目前的研究将测试的假设，一个单一的氨基酸残基（在适当的情况下）是专为大多数传感器激酶蛋白在黄曲霉磷酸酶活性所需。由于几乎所有细菌传感器激酶都存在类似的序列，因此拟议的研究将影响对几乎所有细菌中类似系统的理解。该计划是要确定这些残基专门需要激酶和磷酸酶活性在一个家庭的高度相关的TCS信号蛋白在M.黄。生化研究将确定这些系统是否保持绝缘或显示交叉调节。将使用遗传学和生物化学评估相互作用伙伴的网络分析。系统生物学建模工作也将用于预测已识别网络的控制和功能，并可扩展到M.xanthus中的其余信号系统。调研：这项研究的结果将广泛影响信号转导领域，了解复杂环境中的多细胞相互作用，种间相互作用，并通过系统生物学促进其他生物体中信号通路相互作用的识别。学历：该实验室非常重视指导博士后，研究生和本科生，并在培训后将个人置于强大的研究环境中。博士后和学生因其成就获得了奖学金和国家认可。PI在过去十年中参加了多个NSF资助的教育项目，并在国际公认的项目中任教。

Title: Two Component Signal Transduction Networks in Myxococcus xanthusIntellectual Merit: Myxococcus xanthus is a bacterial model for differentiation, intercellular communication, surface motility and bio-complexity. It integrates complex stimuli from its environment to regulate a decision-making process which culminates in formation of stressresistant spores. One critical class of signaling systems is comprised by "two components" (a sensor and a regulator) that directly link environmental stimuli to control of behavior and gene expression. Typically, the sensor and regulator are encoded by genes adjacent to one another on the chromosome and are thus predicted to comprise specific "two-componentsystem" (TCS) to regulate the biology of the cell. M.xanthus encodes at least 144 sensor histidine kinases (HK) and 150 response regulator (RR) proteins, many of which appear to be randomly positioned on the chromosome. As such, M.xanthus possesses one of the most complex and largest repertoires for signal transduction capacity in the bacterial world. Due to significant similarity between these evolutionarily related two-component proteins, prevention of undesired "cross-talk" (aberrant signaling or miscommunication) while also managing bona fide cross-regulation between systems is a critical feature for regulation of M.xanthus community structure. To probe features of TCS that maintain specificity or impart cross-regulation, the proposed study will focus on a subset of highly similar systems in M. xanthus delineated by their presence within gene clusters on the chromosome. Previous work demonstrated complex interactions between two such systems in M.xanthus that affects spore formation. Further dissection of the those pathways led to the finding that the sensor HK functions both as a kinase and as a phosphatase towards its target regulator. The current study will test the hypothesis that a single amino acid residue (in the appropriate context) is exclusively required for phosphatase activity for the majority of sensor kinase proteins in M.xanthus. Because similar sequences exist in nearly all bacterial sensor kinases, the proposed studies will impact understanding of similar systems in nearly all bacteria. The plan is to identify those residues exclusively required for kinase and phosphatase activity in a family of highly related TCS signaling proteins in M.xanthus. Biochemical studies will determine if these systems remain insulated or display cross-regulation. Network analysis of the interacting partners will be assessed using both genetics and biochemistry. A Systems Biology modeling effort will also be utilized to predict control and functionality for identified networks and can be extended to the remainder of the signaling systems in M.xanthus.Broader Impacts. Research: Results from this study will broadly impact the signal transduction field, understanding multicellular interactions in complex environments, interspecies interactions, and facilitate identification of signaling pathway interactions via systems biology in other organisms. Education: The laboratory places a strong emphasis on mentoring postdocs, graduate students, and undergraduates and has a consistent record of placing individuals in strong research environments following their training. Postdocs and students have received fellowships and national recognition for their accomplishments. The PI has participated in multiple NSF-funded educational programs over the past decade and taught in internationally recognized programs.