Unraveling the secrets of Alzheimer’s -amyloid fibrils

P roteins adopt an amazing array of sequence-dependent structures that enable them to perform the many chemical functions critical to life. Over the past decade, however, it has become clear that many different protein sequences can also form misfolded, insoluble aggregates known as amyloid fibrils, with common structural elements. Amyloid fibrils appear to be involved in a number of diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion diseases, and type II diabetes (1). Even ordinary globular proteins (e.g., myoglobin) can form amyloid fibrils under certain conditions (2), suggesting that fibril formation is a previously unappreciated general property of many proteins. Thus, it is of fundamental interest to understand how so many different protein sequences can adopt this alternative structure and it is of medical interest to understand and control disease-related amyloid formation. Knowledge of the three-dimensional structure of amyloid fibrils is critical for understanding the mechanism of fibrillogenesis and for design of possible inhibitors. Unfortunately, amyloid fibrils are noncrystalline and insoluble, and therefore are not amenable to x-ray crystallography and solution NMR, the classic tools of structural biology. In a recent issue of PNAS, Petkova et al. (3) report a structural model for Alzheimer’s -amyloid fibrils deduced primarily from solid-state NMR experiments. This work provides a significant step forward in understanding -amyloid formation and showcases the power of solid-state NMR for obtaining structural information on important but challenging biomolecules. Amyloid fibrils share a number of characteristics, including a crossstructural motif (1). X-ray fiber diffraction data indicate that the fibrils contain -strands that are perpendicular to the fiber axis, with interstrand hydrogen bonding parallel to the fiber axis. However, fiber diffraction cannot determine the chemical details that are needed to understand fibrillogenesis, which parts of the sequence form the -strands and which specific amino acid residues are interacting, and cannot even determine whether the proteins in the fibril adopt a unique, ordered structure. This information has now been deduced by Petkova et al. for Alzheimer’s -amyloid fibrils using a variety of solid-state NMR approaches (3). Solid-state NMR methods are well suited to high-resolution structural measurements on noncrystalline solids. Orientation-dependent spin interactions, which are averaged by rapid tumbling in NMR spectra of molecules in solution, lead to broad resonances in NMR spectra of solids. Solid-state NMR experiments typically employ one of two strategies to narrow the resonances and