MECHANISM OF HEME CAPTURE BY THE HEMOPHORE SECRETED BY PSEUDOMONAS AERUGINOSA

铜绿假单胞菌分泌的血红素捕获血红素的机制

• 批准号: 7959522
• 负责人: Mario Rivera
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959522
• 关键词: Binding; Complex; Computer Retrieval of Information on Scientific Projects Database; Extracellular Space; Funding; Goals; Grant; Heme; Hemoglobin; Human; Indium; Institution; Iron; Mammals; Membrane; Molecular; Play; Proteins; Pseudomonas aeruginosa; Research; Research Personnel; Resources; Role; Source; System; Theft; United States National Institutes of Health; heme a; insight; molecular recognition; pathogenic bacteria; protein protein interaction; protein structure function; receptor; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Heme is the most abundant source of circulating iron in mammals. It is therefore not surprising that many pathogenic bacteria, including the opportunistic Pseudomonas aeruginosa, avidly pursue its capture and internalization to overcome the very low free-iron concentrations encountered in their mammalian hosts. To capture heme, several pathogenic bacteria, including P. aeruginosa, deploy a heme acquisition system (Has), which consists of a protein secreted to the extracellular space (HasAp) and an outer membrane receptor (HasR). HasAp is also termed a hemophore because it efficiently captures hemoglobin-heme and delivers it to the receptor for subsequent internalization. The studies proposed herein aim to achieve fundamental molecular level understanding of the protein-protein interactions that allow HasAp to "steal" heme from human hemoglobin. In particular, the investigators seek to gain unprecedented structural, dynamic and mechanistic insights into the factors that determine the transfer of heme from human hemoglobin to HasAp. This long-range goal will be reached by pursuing two main objectives: 1) Elucidate the three dimensional structure of apo-HasAp, 2) Identify the binding interface of the encounter complex that forms when HasAp binds to hemoglobin, prior to heme transfer, and decipher the role played by the gross reorganization of HasAp structural elements in the molecular recognition and binding to hemoglobin.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 血红素是哺乳动物循环铁最丰富的来源。因此，毫不奇怪的是，许多病原菌，包括机会性铜绿假单胞菌，都热衷于捕获和内化其，以克服哺乳动物宿主中游离铁浓度极低的问题。为了捕获血红素，包括铜绿假单胞菌在内的几种病原菌会部署血红素获取系统 (Has)，该系统由分泌到细胞外空间的蛋白质 (HasAp) 和外膜受体 (HasR) 组成。 HasAp 也被称为血红素，因为它能有效捕获血红蛋白-血红素并将其递送至受体以进行随后的内化。本文提出的研究旨在实现对蛋白质-蛋白质相互作用的基本分子水平理解，从而允许 HasAp 从人类血红蛋白中“窃取”血红素。特别是，研究人员寻求对决定血红素从人类血红蛋白转移到 HasAp 的因素获得前所未有的结构、动态和机制见解。这一长期目标将通过追求两个主要目标来实现：1）阐明apo-HasAp的三维结构，2）在血红素转移之前识别HasAp与血红蛋白结合时形成的相遇复合物的结合界面，并破译HasAp结构元件的总体重组在分子识别和与血红蛋白结合中所起的作用。