The ability of proteins to fold to their functional states is an astonishing example of the power of biological evolution at the molecular level. Despite the large number of different native protein folds, the process of folding can be described in terms of a universal mechanism that appears to be based on the generation of the correct overall topology through interactions involving a relatively small number of residues. Protein misfolding is an intrinsic aspect of normal folding within the complex cellular environment, and its effects are minimized in living systems by the action of a range of protective mechanisms including molecular chaperones and quality control systems. Unfolded and misfolded proteins have a tendency to aggregate to form a variety of species including the highly organized and kinetically stable amyloid fibrils. The latter species represent a generic form of structure resulting from the inherent polymer properties of polypeptide chains, and their formation is associated with a wide range of debilitating human diseases. Amyloid fibrils and their precursors appear to have similar adverse effects on cellular function regardless of the sequence of the component peptide or protein. Our increasing knowledge of the interplay between different forms of protein structure and their generic characteristics provides a platform for rational therapeutic intervention designed to prevent or treat this whole family of diseases.
