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Review
. 1999 Mar 30;96(7):3342-4.
doi: 10.1073/pnas.96.7.3342.

Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease

P T Lansbury Jr
Review

Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease

P T Lansbury Jr. Proc Natl Acad Sci U S A. .
No abstract available

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Figures

Figure 1
Figure 1
A simplified mechanistic scenario highlighting the differences between normal folding and pathogenic fibrillization. The approximate free energy of each species is encoded by color; from the least stable in yellow to the most stable in red. Normal folding occurs by an intermediate-free pathway involving a descent through a funnel-like energy surface to the low-energy folded structure. The fibrillogenic intermediate depicted as an orange rectangle will not accumulate under normal circumstances. However, point mutations in the protein sequence could stabilize this species relative to the folded state, for example, by increasing the rate of unfolding of the native state. Fibril formation will not occur, however, unless a critical concentration of this intermediate accumulates. With respect to pathogenic fibrillization, structured intermediates, designated protofibrils, are populated during the process, an important distinction between the pathways. The intermediate protofibrils grow slowly, then are rapidly converted to large amyloid fibrils (4).
Figure 2
Figure 2
A “toxic intermediate” proposal for the underlying etiology of degenerative disease, motivated by consideration of the evolved energetics of protein folding, as discussed in the text. The small arrows topped by questions marks are meant to indicate uncertainty regarding the potential importance of slight biological activity of the fibril and the possibility that cell death could trigger the protofibril-to-fibril transition.
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