Proteostasis

Proteostasis, a portmanteau of the words protein and homeostasis, is the concept that there are competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking and degradation of proteins present within and outside the cell. The concept of proteostasis maintenance is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therefore, adapting proteostasis should enable the restoration of proteostasis once its loss leads to pathology. Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostasis perturbations by pathogens such as viruses. Mechanisms by which proteostasis is ensured include regulated protein translation, chaperone assisted protein folding and protein degradation pathways. Adjusting each of these mechanisms to the demand for proteins is essential to maintain all cellular functions relying on a correctly folded proteome. Proteostasis, a portmanteau of the words protein and homeostasis, is the concept that there are competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking and degradation of proteins present within and outside the cell. The concept of proteostasis maintenance is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therefore, adapting proteostasis should enable the restoration of proteostasis once its loss leads to pathology. Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostasis perturbations by pathogens such as viruses. Mechanisms by which proteostasis is ensured include regulated protein translation, chaperone assisted protein folding and protein degradation pathways. Adjusting each of these mechanisms to the demand for proteins is essential to maintain all cellular functions relying on a correctly folded proteome. One of the first points of regulation for proteostasis is during translation. This is accomplished via the structure of the ribosome, a complex central to translation. These two characteristics shape the way the protein folds and influences the proteins future interactions. The synthesis of a new peptide chain using the ribosome is very slow and the ribosome can even be stalled when it encounters a rare codon, a codon found at low concentrations in the cell. These pauses provide an opportunity for an individual protein domain to have the necessary time to become folded before the production of following domains. This facilitates the correct folding of multi-domain proteins.The newly synthesized peptide chain exits the ribosome into the cellular environment through the narrow ribosome exit channel (width: 10Å to 20Å, length 80Å). Due to space restriction in the exit channel the nascent chain already forms secondary and limited tertiary structures. For example, an alpha helix is one such structural property that is commonly induced in this exit channel. At the same time the exit channel also prevents premature folding by impeding large scale interactions within the peptide chain which would require more space. In order to maintain protein homeostasis post-translationally, the cell makes use of molecular chaperones sometimes including chaperonins, which aid in the assembly or disassembly of proteins. They recognize exposed segments of hydrophobic amino acids in the nascent peptide chain and then work to promote the proper formation of noncovalent interactions that lead to the desired folded state. Chaperones begin to assist in protein folding as soon as a nascent chain longer than 60 amino acids emerges from the ribosome exit channel. One of the most studied ribosome binding chaperones is trigger factor. Trigger factor works to stabilize the peptide, promotes its folding, prevents aggregation, and promotes refolding of denatured model substrates. Trigger factor not only directly works to properly fold the protein but also recruits other chaperones to the ribosome, such as Hsp70. Hsp70 surrounds an unfolded peptide chain, thereby preventing aggregation and promoting folding. Chaperonins are a special class of chaperones that promote native state folding by cyclically encapsulating the peptide chain. Chaperonins are divided into two groups. Group 1 chaperonins are commonly found in bacteria, chloroplasts, and mitochondria. Group 2 chaperonins are found in both the cytosol of eukaryotic cells as well as in archaea. Group 2 chaperonins also contain an additional helical component which acts as a lid for the cylindrical protein chamber, unlike Group 1 which instead relies on an extra cochaperone to act as a lid. All chaperonins exhibit two states (open and closed), between which they can cycle. This cycling process is important during the folding of an individual polypeptide chain as it helps to avoid undesired interactions as well as to prevent the peptide from entering into kinetically trapped states. The third component of the proteostasis network is the protein degradation machinery. Protein degradation occurs in proteostasis when the cellular signals indicate the need to decrease overall cellular protein levels. The effects of protein degradation can be local, with the cell only experiencing effects from the loss of the degraded protein itself or widespread, with the entire protein landscape changing due to loss of other proteins’ interactions with the degraded protein. Multiple substrates are targets for proteostatic degradation. These degradable substrates include nonfunctional protein fragments produced from ribosomal stalling during translation, misfolded or unfolded proteins, aggregated proteins, and proteins that are no longer needed to carry out cellular function. Several different pathways exist for carrying out these degradation processes. When proteins are determined to be unfolded or misfolded, they are typically degraded via the unfolded protein response (UPR) or endoplasmic-reticulum-associated protein degradation (ERAD). Substrates that are unfolded, misfolded, or no longer required for cellular function can also be ubiquitin tagged for degradation by ATP dependent proteases, such as the proteasome in eukaryotes or ClpXP in prokaryotes. Autophagy, or self engulfment, lysosomal targeting, and phagocytosis (engulfment of waste products by other cells) can also be used as proteostatic degradation mechanisms.