Interactions of the Amyloid-forming Peptide PAP248-286 with Lipid Membranes: Relating Biophysical Mechanism to Biological Activities

Abstract

The interactions of membrane active peptides with lipid membranes are critical to both normal biological function and to the pathogenesis of many debilitating diseases. Antimicrobial peptides (AMPs), important players in innate immunity, provide protection from microbial infection through a variety of mechanisms, including membrane disruption and bacterial agglutination. On the other hand, lipid membranes can both accelerate amyloid formation and be the targets of toxic amyloid-forming peptides that have been implicated in diseases like Alzheimer’s and Parkinson’s diseases. Interestingly, AMPs and amyloid-forming peptides may exhibit some physiologically relevant functional overlap. Both classes of peptides share physicochemical properties that allow them to interact with lipid membranes in a similar manner. These interactions with lipid membranes are thought to drive each peptide’s specific biological activities. This dissertation explores the ways in which PAP248-286, an amyloid-forming seminal peptide that also displays antimicrobial activities, interacts with lipid membranes. Chapter Two characterizes a co-assembly formed by PAP248-286 and lipid membranes that is distinct from, and forms more readily than, bona fide PAP248-286 amyloid fibrils. This species may account for some, if not all, of the biological activities attributed to its amyloid fibrils. Chapter Three elucidates the mechanism by which PAP248-286 disrupts lipid membranes, perhaps providing an explanation for the lack of direct antimicrobial activity observed for the peptide, while furthering the development of a powerful fluorescence lifetime technique for use in future studies. Finally, Chapter Four includes additional experiments and open questions related to the membrane interactions and antimicrobial activity of PAP248-286.