Amyloid structure--one but not the same: the many levels of fibrillar polymorphism.

Many proteins and peptides can form amyloid-like structures both in vivo and in vitro. Although strikingly similar fibrillar structures can be observed across a variety of amino acid sequences, the fibrils formed often exhibit a stunning wealth of polymorphisms at the level of electron or atomic force microscopy. This appears to violate the Anfinsen principle seen for globular proteins, where each protein sequence codes for just one well-defined fold. To a large extent, polymorphism reflects variable packing of a single protofilament structure in the mature fibrils. However, we and others have recently demonstrated that polymorphism can also reflect real structural differences in the molecular packing of the polypeptide chains leading to several possible protofilament structures and diverse mature fibrillar structures. Glucagon has been a particularly useful model system for studying the fibrillogenesis mechanisms that lead to the formation of structural polymorphism, thanks to its single tryptophan residue and the availability of large quantities at pharmaceutical-grade quality. Combinations of structural investigations and seed extension experiments have revealed the reproducible formation of at least five different self-propagating fibril types from subtle variations in growth conditions. These reflect the underlying complexity of the peptide conformational landscape and provide a link to natively disordered proteins, where structure is dictated by context in the form of different binding partners. Here we review some of the latest advances in the study of glucagon fibrillar polymorphism and their implications for mechanisms of fibril formation in general.