Structure and Function of Membrane-Associated Peptides and Proteins

点击翻译按钮获取中文摘要

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.