Interaction of Amyloidogenic Proteins with Asymmetric Membranes

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Many important biological processes involved the interaction of proteins with cell membranes. It is thought that such interactions have a role in the killing of bacteria by certain anti-bacterial proteins. They may also play an important role in the death of human cells during amyloid diseases such as Alzheimer's disease. The importance of membrane protein interactions extends beyond biology and the templating of specific structures via interactions with membranes has applications in bio-inspired materials. High resolution molecular level studies of the interactions of proteins with membranes could lead to the design of better anti-bacterial agents and the development of novel materials. Unfortunately, investigators have been forced to use relatively crude mimics of biological membranes that do not capture critical aspects of natural cell membranes. In particular, natural cell membranes are asymmetric in the sense that the inside layer of the membrane has a different composition than the outside layer. This effect has important consequences for their behavior. This project will exploit recent technical breakthroughs to study the interactions of a representative member of an important class of human proteins with realistic asymmetric model membranes. The research will provide an unprecedented high resolution view of how proteins interact with biological membranes and induce cell death. The project includes significant efforts devoted to training the next generation of STEM students including initiatives designed to increase undergraduate participation in research and to promote women in the STEM disciplines. The project will define the principles of membrane-catalyzed aggregation of intrinsically disordered polypeptides (IDPs) using biologically relevant asymmetric membranes with a focus on the amyloidogenic polypeptide IAPP. The aggregation of polypeptides on membranes is a general feature of amyloid fiber formation and likely plays a role in the function of certain anti-microbial polypeptides. Unfortunately, existing model membranes are very poor mimics of the relevant plasma membranes. This has hindered biophysical studies of membrane induced self-assembly and membrane activity, making it exceptionally challenging to connect high resolution biophysical studies with the situation in vivo. This project will use asymmetric membranes with physiologically relevant lipid composition and cholesterol together with new methods to probe protein aggregation at high resolution. IAPP is chosen as a model system because it is broadly representative of amyloid formation by IDPs and because of the wealth of biochemical, biophysical and biological data available for this system. The principles that emerge from the research will be applicable to a wide range of systems including other amyloidogenic proteins and anti-microbial peptides. This project is supported by the Molecular Biophysics Cluster of the Division of Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.