Taking the Wrong Path

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Science  27 Apr 2012:
Vol. 336, Issue 6080, pp. 393
DOI: 10.1126/science.336.6080.393-b

Most proteins fold efficiently into their functional native structures either on their own or with the help of a molecular chaperone. Despite quality-control pathways, however, misfolded proteins occur in the cell and are associated with a range of diseases such as Alzheimer's, Parkinson's, and prion disorders. Given the severe consequences of protein misfolding, there is much interest in understanding the mechanisms of misfolding for disease-associated proteins. In prion diseases, a misfolded form of the prion protein, PrP, aggregates and induces conversion of natively folded protein to the misfolded form. Yu et al. used single-molecule force spectroscopy to directly observe the misfolding of PrP. They observed two-state behavior with no evidence of an intermediate on the native folding pathway. Three non-native structures were accessed from the unfolded state, however. These misfolding pathways were explored more frequently than the native pathway, but the misfolded states were rarely occupied because of their instability. A mutant with higher aggregation propensity had a similar folding pathway as the native protein, but two of the misfolded states were more stable in the mutant, which suggests that these states may be involved in aggregation. Applying this approach to other misfolded proteins will give insight into commonalities and differences between misfolding mechanisms.

Proc. Natl. Acad. Sci. U.S.A. 109, 5283 (2012).

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