The deposition of insoluble amyloid fibrils is a well-characterized part of the pathogenesis of more than 100 diseases, but relatively little is known about the mechanisms that underlie fibril formation. Back-to-back articles in the May issue of Nature Structural Biology now give us snapshots of two stages in the pathway to these familiar enemies.
Both studies used NMR spectroscopy to investigate the misfolding and aggregation of β2-microglobulin (β2M). Although it is normally soluble, β2M is found at a high concentration in the amyloid plaques that can form in the musculoskeletal system of patients with chronic renal failure who are receiving long-term haemodialysis. The β2M protein has previously been shown to form amyloid-like fibrils spontaneously under denaturing conditions, and it was an early precursor of these fibrils that was imaged by Radford and colleagues. The study found that β2M amyloid precursors partially retain the double β-sheet structure that is characteristic of the native protein, which implies that these β-sheets might contribute to the cross-β-sheets that are characteristic of mature amyloid fibrils.
By contrast, Gotto and colleagues studied mature β2M fibrils, and developed an extension of the Hydrogen/Deuterium-exchange method to explore the structure of the interior of fibrils at single-residue resolution. At the core of the fibril, they describe an extensively hydrogen-bonded β-sheet, accounting for the great stability of amyloid fibrils.
Recent evidence that implicates early intermediates in the pathway to fibril formation as being culprits in the damage that is caused by amyloid diseases (see, for instance, the further reading below) serves to underscore the importance of understanding not just the nature of the fibrils, but also the stages that lead to their creation.
References
ORIGINAL RESEARCH PAPER
McParland, V. J. et al. Structural properties of an amyloid precursor of β2-microglobulin. Nature Struct. Biol. 9, 326–331 (2002)
Hoshino, M. et al. Mapping the core of the β2-microglobulin amyloid fibril by H/D exchange. Nature Struct. Biol. 9, 332–336 (2002)
FURTHER READING
Bucciantini, M. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511 (2002)
Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002)
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Smith, A. The nature of the beast. Nat Rev Drug Discov 1, 410 (2002). https://doi.org/10.1038/nrd833
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DOI: https://doi.org/10.1038/nrd833