Autophagy: Biology and Diseases by Zheng-Hong Qin

Author:Zheng-Hong Qin
Language: eng
Format: epub
ISBN: 9789811506024
Publisher: Springer Singapore

18.2 Protein Misfolding and Degradation Pathways

18.2.1 Protein Misfolding and Protein Polymer Formation

18.2.1.1 Basic Principles of Protein Folding and Molecular Chaperones

Protein folding refers to the physical process by which proteins form their intrinsic three-dimensional structure from polypeptide chains. According to the law of genetic center, the transmission of biological genetic information is generated by DNA transcription into RNA, which is then translated into polypeptide chains. Polypeptide chains with the complete primary structure are processed and modified, and finally folded to form proteins with specific spatial conformation. Protein usually has a quaternary structure, among which, the primary structure of a protein refers to the sequence of amino acids in the peptide chain, which is the basic structure of protein molecules and the basis of protein spatial structure and function. Protein spatial structure also includes secondary, tertiary and quaternary structure, which is a three-dimensional conformation formed by folding and coiling on the basis of the primary structure. Newly synthesized polypeptide chains in cells can only perform specific biological functions if they are folded correctly to form specific proteins with three-dimensional structures. So why do newborn peptides spontaneously fold to form proteins with a specific spatial conformation? What is the regulatory mechanism for this folding process? At present, it is believed that protein folding is a spontaneous process, which is determined by hydrophobic bond interaction, hydrogen bond formation, van der Waals force, and other factors in the polypeptide chain. The folding process of the new peptide chain follows the “thermodynamic hypothesis” and is controlled by kinetics.

In the 1960s, Anfinsen et al. found in the denaturation and renaturation experiments of bovine pancreas RNA hydrolases that the denaturated RNA hydrolases could renature only by removing the denaturants and reducing agents without the help of any other substances, and the bioactive RNA hydrolases could be formed again. Based on this, Anfinsen proposed the classical “thermodynamic hypothesis” of protein folding, and believed that natural protein polypeptide chain is the most thermodynamically stable form under certain environmental conditions. Since the conformation of natural protein is the lowest or the most stable thermodynamic free energy under certain environmental conditions (such as solution component, PH, temperature, ionic strength, etc.), denatured protein can spontaneously fold to form its natural conformation with biological activity under appropriate environmental conditions. The “thermodynamic hypothesis” of protein folding has been confirmed by some experiments and widely accepted.

With the development of research, it has been found that many protein polypeptides have low renaturation efficiency in vitro and form some non-natural conformations or nonspecific polymers. And the renaturation rate is much lower than the body level. In the 1990s, Joseph et al. proposed the protein folding energy theory and introduced the principle of minimum frustration. Bakei et al. thought that the natural conformation of some proteins might not be the lowest energy or the most stable energy state, and proposed that a protein polypeptide chain might have two low-energy states: one is a kind of natural conformation, the other is a kind of non-natural conformation, and the two mutual

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