Molecular structure of amyloid fibrils: insights from solid-state NMR.
Solid-state nuclear magnetic resonance (NMR) measurements have made major contributions to our understanding of the molecular structures of amyloid fibrils, including fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease, by proteins associated with fungal prions, and by a variety of other polypeptides. Because solid-state NMR techniques can be used to determine interatomic distances (both intramolecular and intermolecular), place constraints on backbone and side-chain torsion angles, and identify tertiary and quaternary contacts, full molecular models for amyloid fibrils can be developed from solid-state NMR data, especially when supplemented by lower-resolution structural constraints from electron microscopy and other sources. In addition, solid-state NMR data can be used as experimental tests of various proposals and hypotheses regarding the mechanisms of amyloid formation, the nature of intermediate structures, and the common structural features within amyloid fibrils. This review introduces the basic experimental and conceptual principles behind solid-state NMR methods that are applicable to amyloid fibrils, reviews the information about amyloid structures that has been obtained to date with these methods, and discusses how solid-state NMR data provide insights into the molecular interactions that stabilize amyloid structures, the generic propensity of polypeptide chains to form amyloid fibrils, and a number of related issues that are of current interest in the amyloid field.
Tycko
Robert
R
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA. robertty@mail.nih.gov
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D055592:Biophysical Phenomena; D001703:Biophysics; D002116:Calcitonin / Q000737:chemistry; D005656:Fungal Proteins / Q000737:chemistry; D005979:Glutathione Peroxidase; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D046912:Multiprotein Complexes; D019906:Nuclear Magnetic Resonance, Biomolecular; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics; D011328:Prions / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics; D051844:alpha-Synuclein / Q000737:chemistry
D000682:Amyloid; D016229:Amyloid beta-Peptides; D005656:Fungal Proteins; C083891:HET-S protein, Podospora anserina; D058228:Islet Amyloid Polypeptide; D046912:Multiprotein Complexes; D011228:Prealbumin; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D002116:Calcitonin; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae