Abstract

Polypeptide chains have a generic capacity to self-associate into linear, non-covalent assemblies termed amyloid fibers. Such fibers give the appearance of violating basic principles of protein folding because they can serve as templates of their own propagation. Regardless of the identity of the starting precursor, the resultant amyloid structures share a number of properties. These include insolubility, protease resistance, chemical resistance and cytotoxicity. Proteins are therefore under selective pressure to avoid this phenomenon and are most commonly associated with diseases of advancing age, such as Alzheimer’s, and diseases associated with medical therapy, such as dialysis related amyloidosis (DRA). In our laboratory, we investigate fibrillogenesis as a biologically relevant chemical reaction. Therefore, understanding the mechanism of assembly requires insight into the structures, energetics and pathways which relate different intermediate states. In general, insights are elusive due to the transient and heterogeneous nature of fibrillogenesis. We are nevertheless able to shed light by combining a range of biophysical approaches and focusing on protein systems ranging from peptide models to globular proteins. The commonality among such investigations reveals the rules governing this class of polymeric assembly.