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.

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.

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