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Understanding Protein Folding: What is it and what are its Implications on Disease?

Writer's picture: biologicalfervorbiologicalfervor
Jul 26, 20246 min read

Written By: Ujala Rehman


Proteins are some of the most complex macronutrients in human biology. From immunological purposes such as antibodies to mechanical support to hormonal responses- they are crucial. Protein folding defines the structure of a protein and has a large hand in our overall health and metabolism.


What is Protein Folding?

Proteins originate from the nucleus, where an mRNA strand carrying the code for a specific protein is created. This is known as Transcription. The strand will then travel to the Endoplasmic Reticulum where ribosomes translate the codes for amino acids into a protein, or a polypeptide.

This fresh state occurring right after Translation is known as the primary structure of a protein, defined simply by the arrangement of amino acids in it.

Eventually, some proteins may fold into the secondary structure where hydrogen bonds between amino acids maintain 3-D shapes such as an alpha helix or a beta-pleated sheet.

These structures are generally strong due to the presence of multiple hydrogen bonds.

The Tertiary Structure is a coiling of the protein which forms a spherical shape. It is stronger than the secondary structure due to the presence of many more bonds:

  • Disulfide Bonds

  • Hydrogen Bonds

  • Ionic Bonds

  • Hydrophobic Interactions

The Quaternary structure is formed when more than one polypeptide chains are assembled and create a more convoluted protein. 

As shown by the intensity of each process taken to intricately coil each polypeptide, folding is integral, but why?


Why the Folding?

Firstly, the tertiary structure of a protein which manifests as a globular shape, and the secondary structure both work to make them soluble. To be able to circulate our body performing tasks needed of them, proteins must be water-soluble. The folding is done in such a way that hydrophobic amino acids repelling water are arranged on the inner side whilst their hydrophilic counterparts stay on the outer side, allowing them to freely interact with it. This also forms the aforementioned hydrophobic interactions between certain amino acids, strengthening the integrity of the protein.

Moreover, the intricacy does not stop there! Parts of the protein acting as binding sites and receptors for identification or transport are exposed allowing it to function normally.

Furthermore, the alpha-helix and beta-pleated structures precisely displace certain volumes of water which keeps the protein more stable. This serves as convenient for other nutrients and molecules traveling through a cell membrane etc.

Additionally, Enzyme action is regulated almost exclusively by the tertiary structure of a protein. The specific arrangement of amino acids is what judges the shape of the active site, the part of the enzyme that is attached to its substrate. On account of being biological catalysts, enzymes are a part of nearly every reaction.

The given processes play a major role in healthy living, as shown by the extent of problems caused when they are not performed.


Misfolding: How does it Happen?

Alas, it is quite impossible to keep the labyrinth of biological functions within us always running smoothly. As a result, every now and then newly formed polypeptides will have trouble folding properly.

This can be caused by a multitude of reasons. Random mutations or mistakes occurring during transcription or translation can make some proteins less likely to fold correctly. In fact, this is disturbingly common, with an estimated 1/7 proteins being somehow flawed.

However, a system of proteins known as the Proteasome disposes of such anomalies by turning them back into fragments of amino acids. Despite being mostly reliable, as always, it is not guaranteed to deal with all these misfolded proteins.

The scenario where a misfolded protein is not destroyed can create an array of issues.

For example, if too many proteins suffer the same fate and become virtually useless, a cell may not be able to perform a function efficiently enough. Other times, rather than just losing function, certain misfolded proteins may become dangerous. This can end up causing or being a risk factor for a plethora of illnesses.


Degenerative Diseases

A degenerative disease is the result of protein misfolding. In some cases, this misfolding will lead to proteins being wasted. An excess of this will cause the cell to severely underperform certain functions.

One such example is Marfan Syndrome, a rare genetic disorder caused by a mutation in the gene coding for fibrillin protein. Due to this protein becoming defective, people with the disease have extreme growth and cardiovascular problems. 

Other diseases falling in this category include Cystic Fibrosis and Tay-Sachs disease. These are all genetic, caused by inherited mutations which create problems in the natural protein folding process.



Certain cancers also fall into this category. Evasive misfolded proteins can result in excessive and uncontrolled cell growth, which eventually develops into a tumor.









Figure 2.Visual representation of someone with Marfan Syndrome


Degenerative Nerve Diseases

On the other hand, many other illnesses caused by this phenomenon are known as Degenerative Nerve Diseases.

These are thought to be related to another type of protein misfolding. In this case, instead of becoming a non-participating, dysfunctional molecule, the protein will start displaying its hydrophobic regions on the outside, which may lead to it forming bond with others. In the process known as Aggregation, these proteins use hydrophobic interactions to stick with one another in large groups.

Medical professionals have strong reason to believe that this process plays a not-yet-discovered role in neurodegeneration. This could be due to the diseases being genetic or for multiple other reasons.

Some of these specific diseases may be quite familiar to you, either due to their seemingly inevitable nature or the sheer brutality of their effects. 

They are usually caused by age and genetics. Amongst these diseases are Alzheimer’s and Parkinson’s disease. They can be spotted by a lack of cognitive wellness and memory loss in elderly people.

Unfortunately, these diseases are incurable.

 Despite treatment options ranging from preventative measures to routine medication being available, it is not possible to ‘fix’ them. 

Figure 3.The number of deaths from Parkinsons' disease over time in the USA alone



Degenerative Nerve diseases have an increased hold now and are expected to continue rising in the population due to humans having a higher lifespan and there being a increase in the overall elderly populace.

Prion Diseases are a much more obvious and interesting manifestation of the dangers of protein misfolding. They are caused by aggregating proteins which develop into prions. Furthermore, they trigger proteins in the brain to start folding abnormally. Following the beginning of the diseases, infected individuals experience signs of dementia, hallucinations and severe personality changes.

Despite being quite uncommon, the diseases are fatal and for the most part incurable. What sets it apart is that they are not purely genetic unlike some of the previously discussed examples. Rather, they can even be contracted by eating meat infected with “Mad Cow disease”.

The most common human prion disease is Creutzfeldt-Jakob disease, or simply CJD. It usually occurs sporadically so that the cause is unknown. Unfortunately, not much effective treatment for CJD has yet been discovered.

On a brighter note, when there is so many unanswered questions, it gives everyone a chance to work on an answer. 


The Future of Research in Protein Folding

Due to being such a pressing issue in modern day Biology, various individuals from around the world are collaborating to try and investigate the concept of protein folding. If the research is accurate, we can possibly upgrade to the root of the issue. We can try to find the core of such fatal diseases and eradicate them.

From the field of computational biology, scientists are working on trying to use algorithms to sketch out folding patterns, and their predictions are developing day by day!

Gene therapy is growing to show promise as a way to have more control over random mutations which serve as the root for many rising issues. It is being worked on tirelessly and is making huge amounts of progress.

The idea of Protein Folding kinetics is also used to try and judge the speed of folding simply from the molecule’s topographical structure. By carefully observing the loops and the speeds at which they are formed, we can familiarize ourselves with the natural behavior of a protein. This makes it easier to intervene and prevent abnormalities.


How can you Incentivize this Information?

On a more social level, this information is crucial to everyone. Awareness is the best tool to have. It is time we speculate on the health and safety of the people most vulnerable to such diseases: elders. 

Encourage yourself to take preventative measures against such diseases and spread it to the elders around you.

There are multiple things which can be done to lower the risks:

  • Eating a healthy diet to avoid risk factors such as strokes and cardiovascular problems

  • Keep moving to avoid a sedentary lifestyle

  • Take out time to check in with your healthcare provider.

If possible, be aware of your genetic history as it will allow you to personalize your lifestyle according to what suits you the best.

Knowledge of protein structure must be widespread simply due to how much of a grip it has on human life. Knowing is half the battle, and the war against disease will rage on for a long time.





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