Mechanisms of amyloid formation revealed by solution NMR.
Amyloid fibrils are proteinaceous elongated aggregates involved in more than fifty human diseases. Recent advances in electron microscopy and solid state NMR have allowed the characterization of fibril structures to different extents of refinement. However, structural details about the mechanism of fibril formation remain relatively poorly defined. This is mainly due to the complex, heterogeneous and transient nature of the species responsible for assembly; properties that make them difficult to detect and characterize in structural detail using biophysical techniques. The ability of solution NMR spectroscopy to investigate exchange between multiple protein states, to characterize transient and low-population species, and to study high molecular weight assemblies, render NMR an invaluable technique for studies of amyloid assembly. In this article we review state-of-the-art solution NMR methods for investigations of: (a) protein dynamics that lead to the formation of aggregation-prone species; (b) amyloidogenic intrinsically disordered proteins; and (c) protein-protein interactions on pathway to fibril formation. Together, these topics highlight the power and potential of NMR to provide atomic level information about the molecular mechanisms of one of the most fascinating problems in structural biology.
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address: T.Karamanos@leeds.ac.uk.
Theodoros K
TK
Karamanos
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Arnout P
AP
Kalverda
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Gary S
GS
Thompson
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address: s.e.radford@leeds.ac.uk.
Sheena E
SE
Radford
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods
D000682:Amyloid
Amyloid fibrils; Dynamic interactions; Intrisically disordered proteins; Invisible states; NMR spectroscopy