Structure, self-assembly properties and mechanism of action of antimicrobial peptides, amyloid peptides and silk proteins

抗菌肽、淀粉样肽和丝蛋白的结构、自组装特性和作用机制

• 批准号: RGPIN-2015-04721
• 负责人: Auger, Michèle
• 金额: $ 4.3万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=644314
• 关键词: Structure; self; assembly; properties; mechanism

Our research program focuses on the determination of the structure, self-assembly properties and mechanism of action of several peptides and proteins of biomedical interest. We will focus on antibiotic resistance and neurodegenerative diseases that rely on the structure and assembly of peptides/proteins. We will also study the natural and synthetic production of silk to help in developing biomaterials, especially implants and scaffolds for tissue regeneration. These systems will be investigated by a combination of novel solid-state nuclear magnetic resonance approaches and complementary information will be obtained by several other biophysical techniques.****The dramatic increase in multi-drug-resistant bacteria has led to considerable efforts to find new therapeutic approaches. The design of new antibiotics with novel modes of action is therefore mandatory to fight against microbial infections and antimicrobial peptides are promising candidates. The structure and membrane interactions of synthetic amphipathic peptides will be investigated. More specifically, we will investigate the structure, membrane topology and oligomerization of both lysine-substituted and arginine-substituted peptides.****Comparing the mode of action of natural vs. synthetic antimicrobial peptides is of great interest. We will investigate the interaction of a natural antimicrobial peptide, thanatin, with lipid membranes that model eukaryotic and prokaryotic cells. Since thanatin induces the agglutination of bacteria in vivo, the aggregation of unilamellar lipid vesicles of different compositions will be followed, as well as the secondary structure of the peptide and its membrane interactions.*****Amyloidosis refers to a family of degenerative diseases, including Alzheimer's and Parkinson's diseases, which demonstrate amyloid protein deposits on tissues resulting from the abnormal self-assembly and deposition of proteins into insoluble aggregates known as amyloid fibrils. We propose to investigate the structure and self-assembly properties of two amyloid peptides in solution and associated with membranes, namely a fragment of the protein a-synuclein involved in Parkinson's disease and a fragment of the protein transthyretin involved in different amyloidoses.****Spider silk refers to a range of biological materials made of fibrous proteins that self-assemble in a hierarchical manner to produce various fibers with exceptional mechanical properties and promising applications such as stitches, ligaments and tendons from tissue engineering. We will investigate the structure, thermal stability and aggregation kinetics of recombinant silk proteins in solution. Fibers of flagelliform silk, which forms the capture spiral of orb webs, will also be investigated. We will also determine the structure of the C-terminal domain of silk proteins both in solution and as nanocrystals.***

我们的研究计划侧重于确定几种具有生物医学意义的肽和蛋白质的结构，自组装特性和作用机制。我们将专注于抗生素耐药性和依赖于肽/蛋白质的结构和组装的神经退行性疾病。我们还将研究天然和合成的蚕丝生产，以帮助开发生物材料，特别是用于组织再生的植入物和支架。这些系统将通过结合新的固态核磁共振方法进行研究，并通过其他几种生物物理技术获得补充信息。多重耐药细菌的急剧增加导致了寻找新治疗方法的巨大努力。因此，设计具有新作用模式的新抗生素是对抗微生物感染的强制性措施，而抗微生物肽是有希望的候选者。本研究将探讨人工合成之两亲性胜肽之结构与膜相互作用。更具体地说，我们将研究赖氨酸取代和精氨酸取代肽的结构、膜拓扑结构和寡聚化。*比较天然与合成抗微生物肽的作用模式是非常有趣的。我们将研究一种天然的抗菌肽，thanatin，与脂质膜模型真核和原核细胞的相互作用。由于thanatin在体内诱导细菌凝集，因此将跟踪不同组成的单层脂质囊泡的聚集，以及肽的二级结构及其膜相互作用。淀粉样变性是指变性疾病的家族，包括阿尔茨海默病和帕金森病，其证明淀粉样蛋白沉积在组织上，这是由蛋白质异常自组装和沉积成称为淀粉样蛋白原纤维的不溶性聚集体引起的。我们建议研究两种淀粉样肽在溶液中和与膜相关的结构和自组装特性，即参与帕金森病的蛋白质a-突触核蛋白的片段和参与不同淀粉样变性的蛋白质转甲状腺素蛋白的片段。蜘蛛丝是指由纤维蛋白质制成的一系列生物材料，这些纤维蛋白质以分层方式自组装，以产生具有特殊机械性能和有前途的应用的各种纤维，如组织工程中的缝线，韧带和肌腱。我们将研究重组丝蛋白在溶液中的结构、热稳定性和聚集动力学。我们也将研究鞭毛状丝的纤维，它形成了圆网的捕获螺旋。我们还将确定溶液和纳米晶体中丝蛋白C-末端结构域的结构。*