Structure and Function of Membrane-Associated Peptides and Proteins

每一个活细胞都被一层膜所包裹。因此，大多数生物过程要么发生在膜上，要么需要通过膜。事实上，大约三分之一的蛋白质是膜肽或蛋白质。尽管它们的重要性相对较少的是知道这些蛋白质的三维结构。了解蛋白质的结构及其与其他伙伴（即膜或其他蛋白质）的相互作用是理解功能所必需的，这反过来又是开发新疗法以对抗疾病所必需的。我们的研究计划的目标是表征生物膜的结构，相互作用和功能之间的基本相互作用。尽管与膜蛋白相关的工作面临许多挑战，但我们通过研究脂质环境中的一些重要生物分子，在这一研究领域取得了长足的进步。我们的方法涉及使用新的固态NMR技术，以及其他生物物理方法，在生物相关的磷脂环境中直接研究这些系统。** 本提案描述了我们对当今加拿大社会面临的三个重大问题的贡献，涉及膜相关肽/蛋白质：1）发现新型抗菌肽以对抗不断上升的细菌耐药性; 2）开发创新的免疫调节和抗生物膜肽以对抗感染; 3）研究病毒蛋白以根除多发性硬化症。** 在过去的6年里，我们通过研究这些肽如何杀死细菌，在抗菌肽研究领域做出了许多贡献。未来的工作将包括通过确定它们的结构以及它们如何扰乱膜来研究更有效的抗菌肽（来自aurein 2.2）的作用机制。** 在免疫调节和抗生物膜肽领域，我们在2010年证明了IDR-1018的功能与其在脂质中的结构直接相关。未来的工作将涉及了解另一种具有免疫调节活性的金精衍生物是如何工作的，并基于这一知识开发新的肽。这些研究代表了一个新兴的研究领域。最后，我们最近测试了一个假设，即U24，一种来自人类疱疹病毒的膜蛋白，可能与多发性硬化症（MS）有关，因为它能够与调节神经元发育和健康的其他蛋白质（例如Fyn-SH 3，WW结构域）相互作用。未来的工作将涉及通过核磁共振确定膜中U24的完整结构，并进一步了解U24对神经元的影响。*总的来说，我们的研究计划利用（生物）物理化学来了解膜相关肽/蛋白质的工作原理。这些基本知识对于为细菌耐药性上升、棘手的感染和MS等疾病提供未来的解决方案至关重要。

Every living cell is enveloped by a membrane. Therefore most biological processes either occur at or require transit through a membrane. Indeed, about a third of all proteins are membrane peptides or proteins. Despite their importance relatively little is known about the three-dimensional architecture of these proteins. Knowledge of the structure of a protein and its interaction with other partners (i.e. the membrane or other proteins) is needed to understand function, which is in turn necessary to develop novel therapeutics to combat diseases.******The goal of our research program is to characterize the fundamental interplay between structure, interactions, and function in biological membranes. Despite the many challenges associated with working with membrane proteins, we have made great strides in this research area by studying a number of important biomolecules in their lipid environments. Our approach involves the use of novel solid-state NMR techniques, as well as other biophysical methods, for the direct study of these systems in biologically-relevant phospholipid environments. ******This proposal describes our contribution to three significant problems facing Canadian society today, involving membrane-associated peptide/proteins: 1) the discovery of novel antimicrobial peptides to combat rising bacterial resistance; 2) the development of innovative immunomodulatory and anti-biofilm peptides to fight infections; and 3) the study of viral proteins to eradicate multiple sclerosis. ******Over the last 6 years, we have made a number of contributions in the area of antimicrobial peptide research by investigating how these peptides kill bacteria. Future work will involve examining the mechanism of action of more effective antimicrobial peptides (derived from aurein 2.2), by determining their structure and how they perturb membranes. ******In the area of immunomodulatory and anti-biofilm peptides, we have demonstrated in 2010 that IDR-1018's function is directly correlated to its structure in lipids. Future work will involve understanding how another aurein derivative, which has immunomodulatory activity, works and to develop new peptides based on this knowledge. Such studies represent a burgeoning research area.******Finally, we have recently tested the hypothesis that U24, a membrane protein from Human Herpes Virus, may be implicated in multiple sclerosis (MS), because of its ability to interact with other proteins (e.g. Fyn-SH3, WW domains) that regulate neuronal development and health. Future work will involve determining the full structure of U24 in membranes by NMR and further understanding the impact of U24 on neurons.******Overall, our research program makes use of (bio)physical chemistry to understand how membrane-associated peptides/proteins work. This basic knowledge is essential to provide future solutions to rising bacterial resistance, troublesome infections, and diseases such as MS.