Irreversible protein aggregation, model

Model systems for the study of irreversible protein aggregation... 

Roberts CJ. Kinetics of irreversible protein aggregation analysis of extended Lumry-Eyring models and implications for predicting protein shelf life. J Phys Chem B 2003 107 1194-1207. 

If aggregation is important, the Lumry-Eyring model has to be extended by introducing a folding intermediate I, which can lead reversibly either to the native protein N, or the fully unfolded protein U, or irreversibly to a protein aggregate An, assumed catalytically inactive. The kinetic representation is thus expressed by Eq. (17.28). 

One way to describe the unfolding process is the two-state model shown in Figure 4. It is an equilibrium, a single-transition step between the folded native (N) and the disordered, unfolded or denatured (D) species (36-38). An intermediate step, the formation of possible intermediates (I), can be present between the transformation from N to D. The intermediate state (I) has often been described as the molten globule, for example, for growth hormone (39). It is a stable compact, partly denatured species, which retains some ordered secondary structure but not the tertiary structure of the native protein (35,36,40,41). The aggregate (A) formed may occur from irreversible changes to the unfolded species (18,42-44). 

The prion protein, therefore, exhibits a phase transition from a monomeric protein to an aggregated protein that bears analogy in fundamental respects to the phase transition exhibited by the model proteins discussed in Chapter 5. For the phase transition of our model proteins, association is relatively fast and dissociation or dissolution is quite slow. The difference with the prion phase transition is only qualitative in that the association step of the phase transition of prion protein is extremely slow, and dissociation is so slow as to be irreversible. The slow relentless growth of insoluble prion protein fibers continues until it destroys the cell or tissue with which it may be associated. This calls to mind sickle cell anemia due to an inverse temperature transition of hemoglobin S wherein intracellular fiber growth distorts and sickles red blood cells and leads to their destruction (see Figure 7.22). 

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