This blog post examines why the process by which proteins form their correct three-dimensional structures determines cellular stability and survival, focusing on the interplay between folding, misfolding, and the quality control system.
When multiple amino acids are linked consecutively, they form a string-like polypeptide. This polypeptide undergoes a process of bending and coiling to form a three-dimensional structure; this structuring process is called folding. A polypeptide with such a three-dimensional structure is called a protein. Each protein must properly adopt its specific three-dimensional structure to perform its intended function.
Protein production involves ribosomes and chaperones. Ribosomes synthesize polypeptides by linking individual amino acids produced within the cell, based on the genetic sequence information provided by the cell nucleus. Among these newly synthesized polypeptides, some spontaneously fold into functional proteins, while polypeptides that cannot fold on their own are assisted by chaperones to adopt their correct structure. Various types of chaperones exist within the cell, each acting on different polypeptides.
In most cases, polypeptide folding proceeds normally. However, under specific conditions, polypeptides may fail to fold properly, becoming entangled and forming aggregated clumps. Furthermore, when cells are subjected to stressors such as heat, heavy metals, or chemicals, abnormalities can occur in the structure of proteins either in the folding process or already formed. In such cases, misfolding occurs, where the protein adopts an abnormal three-dimensional structure, or unfolding occurs, where the structure completely disassembles. Proteins with altered structures are termed denatured proteins. Denatured proteins often exhibit exposed hydrophobic amino acids on their molecular surfaces due to the disruption of their three-dimensional structure. The hydrophobic amino acids exposed on the surface of denatured protein molecules interact with each other, causing them to aggregate into insoluble clusters in water. This aggregation process is mostly irreversible; once formed, the aggregates cannot easily escape their aggregated state.
Refolding is the process by which chaperones inhibit aggregate formation and restore denatured proteins to their native structure. Refolding can be reproduced in experimental settings even without chaperones.
Cells possess a quality control system to remove misproduced proteins or regenerate and degrade denatured proteins. When denatured proteins accumulate inside the endoplasmic reticulum (ER), one of the primary organs responsible for this quality control function, this acts as stress on the ER. Resolution of ER stress occurs through various pathways.
When denatured proteins accumulate in the ER, ATF6 is activated, promoting the production of ER chaperones. These chaperones then regenerate the denatured proteins into normal proteins through refolding. Denatured proteins that cannot be restored trigger the sequential activation of IRE1 and XBP-1, which activates the protein degradation machinery. During this degradation process, denatured proteins that are difficult to restore are transported back into the cytoplasm and degraded by the ubiquitin-proteasome system. Furthermore, if the environment causing endoplasmic reticulum stress persists and misfolded protein accumulation continues, PERK is activated. Subsequently, eIF2α, a protein synthesis initiation factor, is inactivated (phosphorylated), preventing further protein synthesis on the ribosome. As a result, the ribosome’s protein synthesis function halts, and the production of misfolded proteins itself decreases. When protein quality control can no longer cope despite these diverse mechanisms, the cell may choose to undergo apoptosis as a last resort.
