NMR Studies of Bacterial Regulatory Proteins

细菌调节蛋白的核磁共振研究

• 批准号: 6864371
• 负责人: John Cavanagh
• 金额: $ 22.72万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864371
• 关键词: NMR; Studies; Bacterial; Regulatory; Proteins

DESCRIPTION (provided by applicant): The research plan described in this competitive renewal application continues successful investigations into the function of proteins involved in bacterial response and protection. For the most part, the proposed studies concentrate on the signal transduction pathway responsible for initiating sporulation in a variety of organisms. Self protection by endospore formation requires an enormous commitment of energy in order to change lifestyle and cell morphology, and is not a process bacteria enter into frivolously. Rather, they first enter a period of self-assessment referred to as the transition state, where processes required for both growth and survival are regulated simultaneously. During this period, the cell is managed by a novel class of proteins known as transition state regulators. A single transition state regulator is able to control a multitude of divergent cellular processes by binding to a set of seemingly unrelated promoter elements on a variety of genes, the transition state regulator AbrB will be characterized in terms of its structure, dynamics and DNA-binding propensities. Comparative studies with two homologous proteins, Abh and Spo0VT, will also be undertaken to determine the basis for the differing regulatory profiles of this class of proteins. Continued environmental hostility forces the cell to terminate the transition state and fully enter the sporulation cycle. A signaling cascade known as a multi-component phosphorelay is responsible for this process. At the core of this phosphorelay are four proteins - a kinase, a response regulator (SpoOF), a phosphotransferase (Spo0B) and a second response regulator (Spo0A), encompassing a pair of ubiquitous communication modules referred to as 'two-component systems'. Spo0A, when phosphorylated becomes a transcriptional regulator, forcing the transition state to end by repressing AbrB production. Studies here will focus on understanding the mechanisms of action of SpoOF and Spo0A. The system described is regarded as a paradigm for bacterial signal transduction systems required for environmental sensing, cell cycle control, cell-cell communication and virulence. From a health perspective, this latter point is particularly important. This system is known to be critically involved in the direct regulation of the expression of pathogens or the regulation of adaptive methods to protect against pathogens. Within the phosphorelay, the two component switches are vital for pathogenic development and have become a focal point for understanding and preventing infectious disease; they are also responsible for the development of antibiotic resistance in many bacteria and are potentially crucial in anti-infective design. Furthermore, the Spo0 phosphorelay and the transition state regulator AbrB have recently been found to be critical contributors in the development of inhalation anthrax infection. Our studies will correlate the function of the phosphorelay proteins with their structural and dynamic characteristics and will offer insight into both the onset of sporulation and also the action of transition-state regulators and response regulators in general.

描述（由申请人提供）：此竞争性更新应用中描述的研究计划继续成功地研究了涉及细菌反应和保护的蛋白质的功能。在大多数情况下，拟议的研究集中于负责在各种生物体中引发孢子形成的信号转导途径。为了改变生活方式和细胞的形态，通过内孢子形成进行自我保护需要巨大的能量承诺，并且不是一种过程细菌。相反，他们首先进入一个称为过渡状态的自我评估时期，在这种情况下，同时调节生长和生存所需的过程。在此期间，该细胞由一种新型的蛋白质管理，称为过渡状态调节剂。单个过渡状态调节剂能够通过在各种基因上与一组看似无关的启动子元素结合来控制多种不同的细胞过程，将以其结构，动力学和DNA结合的潜在的方式来表征过渡状态调节子ABRB。还将与两种同源蛋白ABH和SPO0VT进行比较研究，以确定该类别蛋白质不同调节曲线的基础。持续的环境敌对行动迫使细胞终止过渡状态并完全进入孢子周期。被称为多组分磷的信号级联反应是该过程的原因。该磷层的核心是四种蛋白质 - 一种激酶，一个反应调节剂（SPOOF），磷酸转移酶（SPO0B）和第二个反应调节剂（SPO0A），其中包括一对无处不在的通信模块，称为“两组分组系统”。当磷酸化成为转录调节剂时，SPO0A迫使过渡状态通过抑制ABRB的产生结束。这里的研究将着重于理解欺骗和SPO0A的作用机理。所描述的系统被认为是环境传感，细胞周期控制，细胞 - 细胞通信和毒力所需的细菌信号转导系统的范例。从健康的角度来看，后一点尤其重要。已知该系统与病原体表达的直接调节或适应性方法的调节有关，以防止病原体。在磷光体中，两个成分开关对于致病性发育至关重要，并且已成为理解和预防传染病的焦点。它们还负责许多细菌中抗生素耐药性的发展，并且对抗感染设计至关重要。此外，最近发现，SPO0磷层和过渡状态调节剂ABR是吸入炭疽感染发展的关键因素。我们的研究将将磷化蛋白的功能与它们的结构和动态特征相关联，并将深入了解孢子形成的发作，以及过渡状态调节剂和一般的反应调节剂的作用。