[Anomalous Kinetics of Amyloidogenesis Suggest a Competition between Oligomers and Fibrils]
A V Finkelstein1,2, N V Dovidchenko1, O V Galzitskaya1
1Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow oblast, 142290 Russia.
Abstract:
Meisl et al. have recently observed an anomalous dependence of the amyloid formation rate on the protein concentration. A novel mechanism of fibril growth has been proposed by Meisl et al. to explain the abnormality; it consists in the fibril-catalyzed initiation of fibril formation with saturation of catalytic sites at high concentrations of substrates. Our article describes an alternative explanation of the anomalous kinetics, assuming that the formation of metastable oligomers competes with fibril formation by decreasing the concentration of free monomers. Oligomers are indeed observed in the course of amyloid formation, but are usually considered as seeds of amyloid fibrils rather as their competitors. However, the oligomers visually detectable by electron microscopy were shown to be close in size to those that can be derived from the anomalous dependence of the amyloid growth rate on the protein concentration, given that the anomaly results from competition between oligomer formation and amyloidogenesis.
Insights
Researchers propose a new model for amyloid formation, suggesting that metastable oligomers, not just fibril growth, explain anomalous protein concentration effects. This competition impacts amyloidogenesis kinetics.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Amyloid formation is implicated in various diseases.
- An anomalous dependence of amyloid formation rate on protein concentration has been observed.
- A fibril-catalyzed initiation mechanism with saturation has been proposed to explain this anomaly.
Purpose of the Study:
- To propose an alternative explanation for the anomalous kinetics of amyloid formation.
- To investigate the role of metastable oligomers in amyloidogenesis.
Main Methods:
- Theoretical modeling of amyloid formation kinetics.
- Analysis of the anomalous dependence of amyloid growth rate on protein concentration.
- Comparison of predicted oligomer sizes with experimentally observed sizes.
Main Results:
- The proposed model explains the anomalous kinetics by considering the competition between oligomer formation and fibril formation.
- Metastable oligomers decrease the concentration of free monomers available for fibril growth.
- The size of oligomers derived from the anomalous kinetics is consistent with those observed via electron microscopy.
Conclusions:
- Metastable oligomer formation provides a viable alternative explanation for the observed anomalous amyloid formation kinetics.
- Oligomers may act as competitors to fibril formation rather than solely as seeds.
- This finding offers new insights into the complex mechanisms of amyloidogenesis.
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