How Does a4B1 Integrin Regulate Cell Migration?

蛋白质靶向和跨脂双层转运是一种基本的能量需求 在所有有机体中都有这个过程。生物体蛋白质组中高达约一半的蛋白质 通过蛋白质转运系统插入或跨膜运输，或者 变性人。存在许多不同类型的转位系统，它们允许大蛋白 分子可以在不影响膜通透性的情况下穿过膜 对离子、代谢中间体和其他大分子具有阻隔作用。为了进一步 扩展我们对存在的分子机制的知识，这些分子机制可以 分子跨膜，这项拟议的研究将检查细菌的孪生兄弟- 精氨酸转位(TAT)出口系统。TAT系统传输全折叠和 组装的蛋白质。Tat系统运输的蛋白质数量是高度多样化的。 依赖，从无到多(&gt；100)。缺乏功能齐全的TAT系统 通常会导致宿主细菌的生长缺陷。此外，TAT机器负责 对于出口众多细菌的毒力因子对人类健康具有重要意义。在一个 特别引人注目的例子是，需要一个功能齐全的TAT系统来实现 结核分枝杆菌，结核病的病原体。按TAT运输 该系统最低限度需要三种蛋白质，Tala、Tats和TatC。占主导地位的假设是 TatBC复合体作为受体，识别运输的前序列 底物，而Tala低聚物提供一个门控孔，货物蛋白通过该孔 穿过膜双层。进一步了解机械原理的基本原理 管理通过TAT系统的运输，我们将：(1)探测前体与脂质的相互作用 和转位子，通过将荧光染料附着在前序列上；(2)调查 货物大小和形状对运输速度和运输效率的作用；以及(3)调查 转运子-货物相互作用，通过荧光共振能量转移。 预计调查将大大增加我们对货物是如何 由TAT系统识别，以及哪些类型的货物可以转运。此外, 他们将进一步阐明转位组分和构象的作用 运输所需的变化。这种对TAT基本特性的表征 移位系统将为今后的工作提供必要的基础，例如 开发针对TAT系统的药物的可能性，或用于TAT的使用 系统在生物技术中的应用，例如蛋白质疗法的表达。

Protein targeting and transport across lipid bilayers is a fundamental energy-requiring process in all organisms. Up to approximately half of the proteins in an organism's proteome are inserted into or transported across membranes by protein translocation systems, or translocons. Many distinct types of translocation systems exist that allow large protein molecules to cross membranes without compromising the membranes' role as a permeability barrier to ions, metabolic intermediates, and other macromolecules. In order to further expand our knowledge of the molecular mechanisms that exist to translocate large molecules across membranes, the proposed research will examine the bacterial twin- arginine translocation (Tat) export system. The Tat system transports fully-folded and assembled proteins. The number of proteins transported by the Tat system is highly species dependent, ranging from none to many (> 100). The absence of a functional Tat system often leads to growth defects in the host bacterium. Further, the Tat machinery is responsible for the export of numerous bacterial virulence factors of human health significance. In a particularly dramatic example, a functional Tat system is required for the growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. Transport by the Tat system minimally requires three proteins, TalA, TatS and TatC. The dominant hypothesis is that a TatBC complex acts as a receptor, which recognizes the presequence of transport substrates, and a TalA oligomer provides a gated pore through which the cargo protein crosses the membrane bilayer. To further understand the basic mechanistic principles governing transport via the Tat system, we will: (1) probe precursor interactions with the lipid and the translocon, by attaching a fluorescence dye to the presequence; (2) investigate the role of cargo size and shape on transport rate and transport efficiency; and (3) investigate translocon-cargo interactions, by fluorescence resonance energy transfer.These investigations are expected to substantially increase our understanding of how cargos are recognized by the Tat system, and what types of cargos can be translocated. In addition, they will further elucidate the role of the translocon components and the conformational changes required for transport. This characterization of the basic properties of the Tat translocation system will provide an essential foundation for future work, such as the possibility of developing drugs that target the Tat system, or for the utilization of the Tat system in biotechnological applications, such as the expression of protein therapeutics.