AI Article Synopsis
- Most proteins can form amyloid-like fibrils in laboratory settings, but how this occurs inside living organisms is still unclear.
- Researchers focused on the protein beta-2-microglobulin at physiological conditions to identify a specific folding intermediate that leads to fibril growth, found to contain a non-native trans-proline isomer.
- Structural analysis revealed this intermediate resembles native proteins but has weakened protective edges, suggesting that understanding these folding pathways could help prevent amyloid-related diseases.
Article Abstract
Although most proteins can assemble into amyloid-like fibrils in vitro under extreme conditions, how proteins form amyloid fibrils in vivo remains unresolved. Identifying rare aggregation-prone species under physiologically relevant conditions and defining their structural properties is therefore an important challenge. By solving the folding mechanism of the naturally amyloidogenic protein beta-2-microglobulin at pH 7.0 and 37 degrees C and correlating the concentrations of different species with the rate of fibril elongation, we identify a specific folding intermediate, containing a non-native trans-proline isomer, as the direct precursor of fibril elongation. Structural analysis using NMR shows that this species is highly native-like but contains perturbation of the edge strands that normally protect beta-sandwich proteins from self-association. The results demonstrate that aggregation pathways can involve self-assembly of highly native-like folding intermediates, and have implications for the prevention of this, and other, amyloid disorders.
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| http://dx.doi.org/10.1038/nsmb1058 | DOI Listing |
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