Proteins are large, complex molecules that regulate almost everything in your body, either directly or indirectly.

They do the majority of the work in cells and are critical for the function, regulation, and structure of tissues and organs.

Proteins are made up of hundreds or even thousands of smaller parts called amino acids, which are linked together in long chains. There are a total of 20 amino acids that can be combined in many different ways to create a protein.

The order in which the amino acids are connected determines the unique structure of a protein and how it functions. Proteins can be categorized according to their function:

Function Description
Antibody Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.
Enzyme Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.
Messenger Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.
Structural component These proteins provide structure and support for cells. On a larger scale, they also allow the body to move.
Transport/storage These proteins bind and carry atoms and small molecules within cells and throughout the body.

How proteins are made

The proteostasis network begins with a ribosome that translates messenger RNA into a protein. The RNA sequence dictates the order of amino acids on the chain, which is the primary structure of the protein.

The chain naturally twists and folds into secondary structures that require the least energy to maintain; this is influenced by the non-covalent interactions of the amino acids in a particular chain. The three most common secondary structures that chains form are α-helixes, β-sheets and turns.

These secondary structures also interact with each other in much the same way that amino acids do, causing the polypeptide to form the 3D folds that create the tertiary structure.

Sometimes, the protein may be guided via a chaperone, which causes it to take a different shape from what it would naturally form. Finally, the tertiary may function alone, or it can join other polypeptides, such as hemoglobin, which has a total of four polypeptides of two kinds. In such cases, this is the quaternary structure of a protein.

What is proteostasis?

Proteostasis comes from a fusion of the words ‘protein’ (a molecule that a cell uses as a machine or scaffolding) and ‘stasis’ (meaning to keep the same). The body tries to keep the production of proteins stable and without any defects; this ideal state is known as proteostasis, a balanced state in which the protein-producing machinery works perfectly.

Proteostasis is maintained via the proteostasis network, a network that is, itself, made up largely of proteins. The proteostasis network attempts to maintain protein production without errors, and it consists of the following elements:

Ribosomes Translates RNA into proteins. This occurs slowly enough to allow secondary structures to form as this change takes place.
Chaperones Guides polypeptides into the correct tertiary and quaternary structures. These include the heat shock proteins, which help other proteins maintain their shape during stress, such as low oxygen, low pH, or extreme heat. This category also includes the co-chaperone molecules, which do not interact directly with the target protein but assist the chaperone to guide the target protein into the correct structural form.
Protein degradation machinery Lysosomes are membrane-wrapped pockets of digestive enzymes that digest and recycle unwanted proteins. Ubiquitin is a medium-sized polypeptide that can be attached to any protein to mark it for regulatory action. Ubiquitin molecules are added to proteins via a series of enzymes, the last of which is tailored to the specific protein. Adding a chain of ubiquitins marks a protein for degradation via the proteasome, a large protein complex that, like lysosomes, can break down proteins into their constituent amino acids.

Loss of proteostasis

Unfortunately, this network is not perfect, and sometimes it fails; when this happens, it can result in too few or too many proteins. It can even lead to misfolded proteins that are bent out of shape and cannot perform their jobs or, worse, cause aberrant behavior in the cell by giving the wrong instructions.

Because these errors in the protein production system accumulate over time, the loss of proteostasis is considered to be a primary reason why we age and why we develop certain age-related diseases [1].

Misfolded proteins typically accumulate and form aggregates, which are clumps of the same or similar proteins that bond to each other. These aggregates play a key role in age-related diseases, such as Alzheimer’s and Parkinson’s, in which they destroy the neurons.

These misfolds happen for many reasons, and environmental stress is one of them. Changes to pH or oxidation can create aberrant protein changes, allowing them to make unwanted bonds with other proteins. Extreme cold or heat can also disrupt the non-covalent interactions between the amino acids, leading to a loss of correct structure.

DNA mutations and transcription errors can both create RNA that codes for the wrong amino acid. The same situation can occur if the wrong amino acid is added to a polypeptide. If the amino acid is structurally important, a mutation can weaken the protein and cause it to become more fragile. A recent example of a gene mutation leading to fragile protein production and an elevated risk of Alzheimer’s is the APOE4 mutation [2].

A loss of chaperones can occur due to a failure to transcribe the correct DNA, and, sometimes, the chaperones get bogged down in protein aggregations and cannot move. This trapping of chaperones is linked to Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.

The loss of degradation can also cause protein aggregation. In an ideal situation, unwanted and misfolded proteins are degraded by the cellular machinery responsible for recycling, but aggregations make this harder to achieve. Aggregates form clumps that protect the interior proteins from being broken down and recycled.

Finally, contagious aggregations can lead to problems. Once clumps of stubborn misfolded protein aggregates are in situ, other proteins that would have been easily broken down and recycled also bond to the aggregate and avoid destruction. Prions are good examples of such proteins and are implicated in a number of diseases, including Creutzfeldt-Jakob disease (CJD).

Conclusion

There are a number of potential approaches in development to address the loss of proteostasis, including chaperone and stabilizer replacement, increasing DNA repair, genome repair, rapamycin, and proteostasis-regulating drugs.

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Yuang, Y. et al. (2018) Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nature Medicine doi:10.1038/s41591-018-0004-z