NMR studies of amyloid interactions

Middleton, David A. (2024) NMR studies of amyloid interactions. Progress in Nuclear Magnetic Resonance Spectroscopy, 144-14. pp. 63-96. ISSN 0079-6565

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Abstract

Amyloid fibrils are insoluble, fibrous nanostructures that accumulate extracellularly in biological tissue during the progression of several human disorders, including Alzheimer’s disease (AD) and type 2 diabetes. Fibrils are assembled from protein monomers via the transient formation of soluble, cytotoxic oligomers, and have a common molecular architecture consisting of a spinal core of hydrogen-bonded protein β-strands. For the past 25 years, NMR spectroscopy has been at the forefront of research into the structure and assembly mechanisms of amyloid aggregates. Until the recent boom in fibril structure analysis by cryo-electron microscopy, solid-state NMR was unrivalled in its ability to provide atomic-level models of amyloid fibril architecture. Solution-state NMR has also provided complementary information on the early stages in the amyloid assembly mechanism. Now, both NMR modalities are proving to be valuable in unravelling the complex interactions between amyloid species and a diverse range of physiological metal ions, molecules and surfaces that influence the assembly pathway, kinetics, morphology and clearance in vivo. Here, an overview is presented of the main applications of solid-state and solution-state NMR for studying the interactions between amyloid proteins and biomembranes, glycosaminoglycan polysaccharides, metal ions, polyphenols, synthetic therapeutics and diagnostics. Key NMR methodology is reviewed along with examples of how to overcome the challenges of detecting interactions with aggregating proteins. The review heralds this new role for NMR in providing a comprehensive and pathologically-relevant view of the interactions between protein and non-protein components of amyloid. Coverage of both solid- and solution-state NMR methods and applications herein will be informative and valuable to the broad communities that are interested in amyloid proteins.