Protein Folding, Misfolding, Aggregation And Amyloid Formation: Mechanisms of Aβ Oligomer Mediated Toxicities

Abstract

Protein folding is one of the most perplexing problems in molecular biology. Protein folding is a complex process through which protein molecule acquires unique native structure which carry out specific biological function. However, recently it has been recognized that some proteins have no single well-defined tertiary structure.These proteins are termed intrinsically disordered protein (IDP) which are involved in regulation and signaling. In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the protein molecule has an astronomical number of possible conformations. Hence, from one calculation, for 100 amino acids polypeptide chain, 1011 years will be required for protein to fold, which is an unrealistic time because in vivo protein folding occurs in seconds or minutes. This is known as Levinthal paradox. To overcome Levinthal paradox, several folding models have been proposed. This includes from classical nucleation-propagation model to folding funnel model. The in vitro and in vivo conditions of protein folding are not the same.This was particularly challenged by the discovery of molecular chaperones that assist in correct folding of protein and if protein still misfolds it is subjected to proteasomal degradation for the maintenance of cell homeostasis. Despite of cellular protein quality control proteins often misfold. This happens due to mutations, changes in environmental conditions and includes many more factors. These misfolded proteins give rise to increase population of partially misfolded intermediates which have exposed hydrophobic residues that interact with complementary intermediates and consequently results in the formation of oligomers thereby proto-fibrils and fibrils. These fibrils are deposited in the brain and CNS leading to the manifestation of neurodegenerative diseases. Keeping above views in mind, in this review I have focused on, various folding models, folding in the cell, misfolding, aggregation and mechanism of Aβ fibril formation. Since Aβ oligomers are now considered as more toxic entities than fibrils. Hence, their mechanisms of toxicities also form the theme of the review.