Two Component Signal Transduction Networks in Myxococcus xanthus

黄色粘球菌中的两部分信号转导网络

• 批准号: 1818761
• 负责人: John Kirby
• 金额: $ 10.84万
• 依托单位: Medical College of Wisconsin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1818761&HistoricalAwards=false
• 关键词: Two; Component; Signal; Transduction; Networks

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.

黄色粘球菌的两组分信号转导网络智力优势：黄色粘球菌是一种分化、细胞间通讯、表面运动和生物复杂性的细菌模型。它整合来自环境的复杂刺激来调节决策过程，最终形成耐胁迫的孢子。一类关键的信号系统由“两个组件”(一个传感器和一个调节器)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，传感器和调节器是由染色体上彼此相邻的基因编码的，因此被预测为组成特定的“双组分系统”(TCS)来调节细胞的生物学。黄曲霉编码至少144个感受器组氨酸蛋白(HK)和150个反应调节蛋白(RR)，其中许多蛋白似乎随机定位在染色体上。因此，黄曲霉拥有细菌世界中最复杂和最大的信号转导能力之一。由于这些进化上相关的两组分蛋白质之间有很大的相似性，因此防止不需要的“串扰”(异常信号或错误通信)，同时也管理系统之间真正的交叉调节是调节黄花草群落结构的关键特征。为了探索保持特异性或传递交叉调节的TCS的特征，拟议的研究将集中在黄曲霉高度相似的系统的子集上，这些系统通过它们在染色体上的基因簇中的存在来描述。以前的工作证明了黄花莲中两个这样的系统之间复杂的相互作用，影响了孢子的形成。对这些途径的进一步剖析导致发现，传感器HK既可以作为一种激酶，也可以作为一种磷酸酶来调节它的靶标。目前的研究将检验假设，即在适当的背景下，单一氨基酸残基是黄色微囊藻中大多数感受器蛋白磷酸酶活性所唯一需要的。由于相似的序列存在于几乎所有的细菌传感器激酶中，拟议的研究将影响对几乎所有细菌中相似系统的理解。该计划是为了确定黄花莲中高度相关的TCS信号蛋白家族中的激酶和磷酸酶活性所独有的残基。生化研究将确定这些系统是保持绝缘还是表现出交叉调节。互动伙伴的网络分析将使用遗传学和生物化学进行评估。系统生物学建模工作也将被用来预测已识别网络的控制和功能，并可扩展到黄曲霉的其余信号系统。研究：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、物种间相互作用，并有助于通过系统生物学识别其他生物中的信号通路相互作用。教育：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的记录始终如一。博士后和学生因他们的成就而获得奖学金和国家认可。在过去的十年里，PI参加了多个由NSF资助的教育项目，并在国际公认的项目中任教。