How Chaperone-Assisted Protein Folding Works
What are chaperone-assisted proteins and what roles do they play in protein folding? Basically, chaperones are a group of proteins essential for promoting cell viability and stability. Thus, they are also responsible for ensuring that various processes such as translocation, degradation, and folding are carried out properly at all times.
Protein Folding and Processing
Protein synthesis starts when the DNA of a gene is transferred to a messenger RNA (mRNA) molecule through the process of transcription. The mRNA, which is a single-stranded copy of the gene, then undergoes translation to produce the protein molecule encoded by the original gene.
However, it is important to note that the synthesis of a polypeptide does not guarantee the production of a functional protein. The polypeptides must fold into the correct three-dimensional conformation, assemble into functional secondary and tertiary complexes (i.e., alpha helices and beta sheets) without aggregating or undergoing degradation, and go through further modifications to ensure the proper localization and function of proteins within the cell.
The Importance of Molecular Chaperones in Protein Folding
While it was previously believed that the amino acid sequence of the mRNA polypeptide chain provided all the information the protein needs to assume the correct three-dimensional configuration, more recent studies have proved otherwise. The intervention of other proteins is necessary to ensure the proper folding of the proteins within the cells – and this is where molecular chaperones come in.
Chaperones are proteins that aid in the proper folding of other proteins by facilitating their assembly without being a part of the resulting complex. These proteins merely acts as catalysts and do not add any information required for the folding process.
How do they do what they do? Chaperones prevent aggregation and incorrect folding by binding to and stabilizing partially or totally unfolded protein polypeptides until the polypeptide chain is fully synthesized. They also ensure the stability of unfolded polypeptide chains as they are transported into the subcellular organelles.
Additionally, chaperones play an essential role in the assembly of proteins containing multiple polypeptide chains, in the production of macromolecular structures, and in promoting and regulating the disaggregation of preformed protein aggregates.
While each of the families of molecular chaperones have their own functions, the “heat shock proteins” (Hsps), particularly the Hsp70 and Hsp60 families, play a significant role in protein folding in prokaryotic and eukaryotic cells.
Hsp70
These chaperone proteins are monomeric in nature and contain two different domains: the N-terminal which contains the ATPase and the C-terminal which binds to the substrate. As ATP hydrolyzes within the N-terminal, the C-terminal opens up and binds to the substrate.
Members of the Hsp70 family are primarily responsible for stabilizing unfolded polypeptide chains during translation and while the polypeptides are transported into various subcellular components (e.g., mitochondria, endoplasmic reticulum). They also prevent protein aggregation by binding the “extended region,” the region of the unfolded polypeptide chain that contain many short segments of hydrophobic residues.
Hsp60
While these chaperone proteins can also bind to exposed hydrophobic residues to form stable but inactive aggregates, they mainly prevent aggregation by isolating unfolded proteins.
Hsp60 (chaperonins) has 14 protein components that form two stacked rings (a “double donut” structure), each with seven proteins. Since the unfolded polypeptide chains are bound within the central cavity of this structure, protein folding can proceed without aggregating with other unfolded proteins.
Chaperonins have two forms: the binding form and the enclosed state. In the binding form, ATP is bound, allowing unfolded proteins to enter into the stacked rings. ATP hydrolysis then activates the enclosed or folding-active state. During this brief period, which approximately lasts for 15 seconds, the proteins are prevented from leaving the chamber and are folded into the correct conformation. Once the enclosed state ends, the properly folded proteins are released into the cytoplasm.
Molecular chaperones are essential to protein folding and can prevent protein aggregation by binding to non-specific proteins. Without their help, there would be many more unfolded or misfolded proteins which may lead to the development of several pathological conditions such as Alzheimer’s, Parkinson’s, and Huntington’s disease, Type 2 diabetes, inherited cataracts, and atherosclerosis.