Dealing with all the various forms of cancer is an ongoing medical trial of trying to push a boulder up a very steep hill. While progress is often very clearly and obviously being made, it is still a struggle to make advancements and no one single treatment is often good enough to solve the problem entirely. Thus, finding additional alternative medical options for treating and potentially outright curing each and any type of cancer when it forms in an individual is a constant area of research in the field of medicine. We may have found plenty of methods to use, but there’s always more that can be done to improve the overall survivability for cancer patients. 

One of those areas of research involves trying to understand and better utilize and employ the body’s natural defense mechanisms against cancer occurring, along with destroying tumorous cells when they do form. Our genome as living organisms do have a number of corrective actions available to at least minimize the risk of cells turning into runaway cancerous growths and one of these actions is tumor suppressing proteins. The protein p53 is a well known member of this group that helps to correct any genetic mutations that could lead to out of control cellular division. But it also has its own internal problems.

Ordering The Intrinsically Disordered

This protein is a part of what are referred to as intrinsically disordered proteins (IDPs), i.e. proteins that don’t follow the normal rules of how they are meant to be formed. In general, basic genetics teaches that proteins are encoded from RNA that comes from our DNA and they are made up of building blocks called amino acids that form strings that then fold themselves into particular shapes called conformations. These shapes are essential for the proteins to carry out their activities, whatever they may be, often because their shape allows them to interact with another protein, enzyme, or other molecular component that fits into the shape the protein is making. There are, however, exceptions and these rogue elements break the normal causal rules of proteins. 

These IDPs themselves have intrinsically disordered domains (IDDs) that define particular areas of activity of a protein’s structure, referred to as a domain. The IDDs inherently lack a consistent type of function and are able to shift from things like recruitment of transcription factors to general cell signaling activity depending on the shifts in their structure. While this may give much broader options for using IDPs in a medical sense, it makes things much more difficult for determining their inherent capabilities as proteins in the first place. 

And none more so than p53 and its massive range of activity in cells for tumor suppression despite there being low total transcription of the protein in the cell. Since its suppression and inactivity is seen in over 60% of all cancers, p53 is known to be a crucial factor for fighting against cancer development. However, the low transcription leads to poor conservation of its structure over evolutionary time and it also has biochemical problems that put it on the cusp of aggregating into solid masses of useless tangled proteins. So, all of that is a problem that desperately needs fixing if we’re going to actually use p53 for its intended biological purpose. 

Cancer and Silk

Researchers at the medical university Karolinska Institutet in Sweden have taken it upon themselves to try and tackle the issue of stabilizing p53 so it can be used for anti-cancer therapy. Their plan was to lower this solubility limit and aggregation problem, along with the conformational instability problem, by fusing the p53 protein to parts of another protein that is highly expressed and has specific resistance to aggregation. While searching throughout the animal kingdom for candidate proteins, they came across the family of proteins called the ampullate spidroins, which are the proteins responsible for forming the dragline silk used by spiders. They contain the right protein domains to interact with p53 and exist in soluble forms with tight folding of the needed domains. 

Thus, their first step was to design DNA constructs that would code for a p53 with a particular end sequence that would allow for interactivity and fusion with the spidroin protein end sequences. This was to fix an issue with IDDs, at least for p53, referred to as “N-terminal disorder”. They used a green fluorescent protein (GFP) sequence tag to allow for identification of when the DNA sequence was being expressed and at what concentrations. Their creation of this fusion protein resulted in a much more tightly folded p53 that, when tested, retained its function in human cancer cell lines by being transported to the nucleus and resisting aggregation breakdown. 

Disordered No Longer

The modified p53 protein not only remained highly effective at its activities in the cell, but it was also possible for the scientists to better understand the multi-faceted groups of things the protein does and how its structure contributes to those activities. This in turn allows for other medical researchers to better utilize the protein to deal with cancer and perhaps modify it further for particular requirements to more easily defend against cancer development. The Karolinska Institutet team plans to further use this strategy of fused protein domains in order to understand how other IDPs function and allow for other complicated areas of protein and disease research to advance in its knowledge of the basic biochemistry of this complicated group of proteins. 

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Photo CCs: Spider web Luc Viatour from Wikimedia Commons

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