Thermodynamics of Protein Fibrillization. Relation to Molecular Basis of Diseases

摘要

In recent years, it has become increasingly clear that a wide range of diseases in humans are due to deviations of various proteins from their native functional conformation and to the formation of improperly folded conformational states that lead, as a rule, to fibrillization and aggregation of these proteins and subsequently to various pathological processes. More than 50 serious diseases are currently known to be due to inadequate folding of proteins, including at least 20 different neurodegenerative diseases. These diseases, called protein conformational diseases, include Alzheimer's disease, Parkinson's disease, encephalopathies due to different prions, type II diabetes, thyroid carcinoma, a large number of amyloidoses and a number of other. These pathologies are designated conformational or misfolding diseases. In spite of the efforts of many investigators, the molecular mechanisms of the conformational diseases are still poorly understood. Biophysical and biochemical approaches to study the mechanism of fibril formation have shown that many proteins can assemble into amyloid -like fibrils under various unphysiological conditions such as low pH, high temperature, presence of detergents, organic solvents, high urea concentrations. Hence, from a wide range of in vitro experiments on peptides and proteins it has been deduced that the formation of amyloid structures is not a rare phenomenon only associated with a small number of diseases, but rather that it reflects a well-defined structural form of the proteins that is an alternative to their native state and which can be adopted by many, if not all, native polypeptide sequences. Exothermic events are usually regarded as indicative of protein aggregation in the protein solutions. It has been shown recently that the formation of amyloid fibrils is accompanied by exothermic heat flow. It is thus reasonable to assume that monomer oligomerization/fibrillization is an aggregation-type process that may potentially caus