Structure and function of Heparin Binding Hemagglutinin from Mycobacterium tuberculosis

结核分枝杆菌肝素结合血凝素的结构和功能

• 批准号: MR/R000255/1
• 负责人: Alfonso De Simone
• 金额: $ 53.81万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR000255%2F1
• 关键词: Structure; function; Heparin; Binding; Hemagglutinin

Tuberculosis (TB) is a leading cause of death worldwide due to a single bacterium, Mycobacterium tuberculosis (MTB). Key aspects of TB pathogenesis include the ability of MTB to disseminate from the site of primary infection (primarily the lungs) to potentially any organ (Russel et al, 2010 Science, 328:852-856) via the interaction of MTB with epithelial cells. This process requires a crucial virulence factor called heparin-binding haemagglutinin adhesin (HBHA, Pethe et al., 2001 Nature 412, 190-194), a protein that is localised at the surface of MTB. In addition to the relevant function in TB, HBHA is considered a crucial target for diagnostic and treatment of TB, which is particularly crucial in view of the growing multi-drug resistance of MTB.Currently the structure of HBHA is unknown. The challenging nature of this study is associated with the complex nature of HBHA that has prevented so far the successful employment of methods able to characterise protein structures. This lack of understanding has in turn hampered the characterisation of the mechanisms by which HBHA promotes the extrapulmonary dissemination of TB. The proposal aims at the ambitious target of resolving the structure of HBHA and the functional mechanism by which this protein promotes the adhesion to epithelial cells within the mechanisms of extrapulmunary dissemination of TB. This is a milestone in TB research that requires overcoming significant experimental challenges. Our research proposal comes at a most opportune time since we now have all the tools, materials and background research to achieve this major goal. We will combine our research programmes in biomolecular nuclear magnetic resonance (NMR) spectroscopy and microbiology to generate a multidisciplinary investigation to reveal the structure, dynamics and topology of HBHA at the surface of MTB membranes as well as the details of the mechanism of adhesion to epithelial cells. The impact of our interdisciplinary study will be significant on the wider academic community studying the underlying molecular mechanisms of TB infection and wider disciplines such as protein science, biochemistry, NMR spectroscopy, microbiology, cellular and molecular biophysics. It is anticipated that the outcomes of this research may directly translate into knowledge leading to new therapeutic and diagnostic approaches for TB.

结核病（TB）是世界范围内由单一细菌结核分枝杆菌（MTB）引起的主要死亡原因。结核发病机制的关键方面包括结核分枝杆菌能够通过结核分枝杆菌与上皮细胞的相互作用从原发感染部位（主要是肺部）传播到潜在的任何器官（Russel等人，2010年《科学》，328:852-856）。这一过程需要一种关键的毒力因子，称为肝素结合血凝素粘连素（HBHA， Pethe等人，2001 Nature 412,190 -194），这种蛋白定位于MTB表面。除了在结核病中的相关功能外，HBHA被认为是结核病诊断和治疗的关键靶点，鉴于MTB日益增长的多药耐药性，这一点尤为重要。目前HBHA的结构尚不清楚。这项研究的挑战性与HBHA的复杂性有关，这阻碍了迄今为止能够表征蛋白质结构的方法的成功应用。这种认识的缺乏反过来又阻碍了HBHA促进结核病肺外传播机制的表征。该提案的目标是解决HBHA的结构和功能机制，通过该蛋白促进肺外传播机制中的上皮细胞粘附。这是结核病研究的一个里程碑，需要克服重大的实验挑战。我们的研究计划来得正是时候，因为我们现在拥有实现这一主要目标的所有工具、材料和背景研究。我们将结合我们在生物分子核磁共振（NMR）波谱和微生物学方面的研究项目，开展多学科研究，揭示结核分枝杆菌膜表面HBHA的结构、动力学和拓扑结构，以及粘附上皮细胞的机制细节。我们的跨学科研究将对更广泛的学术界研究结核病感染的潜在分子机制和更广泛的学科，如蛋白质科学，生物化学，核磁共振波谱学，微生物学，细胞和分子生物物理学产生重大影响。预计这项研究的结果可能直接转化为知识，导致新的结核病治疗和诊断方法。

项目成果

A structural overview of mycobacterial adhesins: Key biomarkers for diagnostics and therapeutics.

分枝杆菌粘附素的结构概述：诊断和治疗的关键生物标志物。

• DOI: 10.1002/pro.3346
• 发表时间: 2018
• 期刊: a publication of the Protein Society
• 作者: Squeglia F

Molecular Biomarkers of Disease for Diagnosis and Drug Development.

用于诊断和药物开发的疾病分子生物标志物。

• DOI: 10.2174/092986732624190927115301
• 发表时间: 2019
• 期刊: Current medicinal chemistry
• 影响因子: 4.1
• 作者: Berisio R

Demonstration of Binding Induced Structural Plasticity in a SH2 Domain.

SH2 域中结合诱导结构塑性的演示。

• DOI: 10.3389/fmolb.2020.00089
• 发表时间: 2020
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Visconti L

Molecular Biomarkers of Disease for Diagnosis and Drug Development

用于诊断和药物开发的疾病分子生物标志物

• DOI: 10.2174/092986732611190628090938
• 发表时间: 2019
• 期刊: Current Medicinal Chemistry
• 影响因子: 4.1
• 作者: Berisio R