Eichner T, Kalverda AP, Thompson GS, Homans SW, Radford SE.
Conformational conversion during amyloid formation at atomic resolution.
Mol Cell. 2011 Jan 21;41(2):161-72.
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This elegant study by Eichner et al. considerably advances atomic-level understanding of the molecular features that underlie human β2-microglobulin (β2m) amyloidogenecity, and should facilitate the development of novel therapeutics for dialysis-related amyloidosis (DRA). Using NMR, they solved a solution structure of an amyloidogenic intermediate of N-terminal truncated β2m (ΔN6), a protein variant that is present in renal amyloid deposits of DRA patients. Furthermore, using NMR, Eichner et al. established specific conformational changes in full-length β2m that arose from bimolecular interactions with ΔN6 that presumably reflected the truncated protein’s prion-like seeding of β2m fibrils. Their findings reinforce that invaluable insight on the molecular basis of amyloidogenic polypeptides can be obtained by probing, at the atomic level, the native and non-native structures and aggregation propensities of pathogenically relevant variants (unmodified and post-translationally modified forms).
In contrast with the central pathogenic role that soluble Aβ oligomers are believed to have in Alzheimer’s disease, the pathogenic process in DRA is likely to be the abundant renal deposition of amyloid that contains β2m fibrils and various accessory molecules. Similar with other amyloidogenic polypeptides, β2m aggregates to form amyloid fibrils via distinct pathways that generate heterogeneous assemblies in dynamic equilibria (1). Nevertheless, this study, and others, suggests that discrete assemblies of ΔN6 are relevant to the disease process. First, greater than 20 percent of β2m in renal amyloid deposits of DRA patients is proteolyzed and contains the truncated ΔN6 form (2). Second, solid-state NMR studies indicate that the non-native trans-prolyl peptide bond at position 32, which is present in the ΔN6 intermediate, is also present in in-vitro generated β2m fibrils (3). Third, ΔN6 forms amyloid fibrils more readily than the full-length protein (4). Fourth, ΔN6 interacts more strongly with collagen than the full-length protein, and β2m amyloid deposits more readily in collagen-rich joints (5). Lastly, Eichner et al. showed that the trans-prolyl ΔN6 intermediate acted in a prion-like manner by specifically seeding fibril formation by the less amyloidogenic full-length β2m. If, indeed, ΔN6 assemblies are a primary culprit for DRA, a novel therapeutic strategy may be reagents that specifically inhibit proteolysis of the N-terminal of β2m.
As mentioned above, more than one assembly of β2m is likely to contribute to DRA. Thus, it would be interesting to establish if the ΔN6 intermediate studied by Eichner et al., or an equivalent full-length β2m assembly, is a pre-nucleus for fibrils or a direct precursor for oligomers that are formed by domain-swapped β2m variants (6,7). Alternatively, the latter conformers may form amyloid fibrils by distinct pathways that reflect the heterogeneous nature of β2m fibrils (8). Lastly, the finding by Eichner et al. that non-native structure in the ΔN6 intermediate is anchored by a propyl-peptide rearrangement is similar to the central role that proline has in stabilizing non-native conformations of several other amyloidogenic proteins, for example, the variable light chain from the κ4 Bence Jones protein, Len (9).
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