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Review
. 2008 Jun;5(3):260-87.
doi: 10.2174/156720508784533312.

Amyloidogenesis of natively unfolded proteins

Vladimir N Uversky  1
Affiliations
Review

Amyloidogenesis of natively unfolded proteins

Vladimir N Uversky. Curr Alzheimer Res. 2008 Jun.

Abstract

Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.

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Figures

Fig. 1
Fig. 1
Intrinsic disorder prediction for human α-synuclein using IUPred (solid line); RONN (dashed line); PONDR VSL2 (dotted line) and PONDR VL3 (dash-dotted line). The results averaged over these for predictions are shown as bold line.
Fig 2
Fig 2
Structural properties and conformational behavior of human α-synuclein. A. Far-UV CD spectra measured under different conditions. B. FTIR spectra measured for natively unfolded, partially folded and fibrilar forms of α-synuclein. C. ANS spectra under different conditions. D. Kratky plot representation of the results of small angle X-ray scattering analysis of α-synuclein at different experimental conditions.
Fig. 3
Fig. 3
Conformational behavior human α-synuclein. A. pH-Induced folding of α-synuclein. B. Temperature-induced folding of the nativley unfolded α-synuclein.
Fig. 4
Fig. 4
A diagram showing the folding energy landscapes of a typical globular protein (A) [1] and of a typical natively unfolded protein in the absence (B) or presence of different binding partners (C). These landscapes are depicted schematically in one-dimensional cross-section.
Fig. 5
Fig. 5
Effect of pH (A) and tempreature (B) on fibrillation of human α-synuclein.
See this image and copyright information in PMC

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