Understanding Cdc48 and Its Role in Serious Diseases

Until recently, not much was known about Cdc48, other than that it was linked to multiple diseases. Certainly, the name doesnâ€™t reveal much about its origin, nature, or functions, which are all crucial to even a basic understanding of what this mysterious entity does. However, recent research has pinpointed Cdc48â€™s role in many serious diseases, prompting many a layperson and scientist alike to wonder how, exactly, Cdc48 has earned the descriptor â€œthe Swiss Army Knife of the Cell.â€

What is Cdc48?

In simplest terms, Cdc48 is a protein, found in large quantities in human cells. First isolated in the early 1980s by David Botstein, Cdc48 has always been thought to play some sort of pivotal role in the progression of the cell cycle, but it wasnâ€™t clear which. Since its discovery, however, the protein has been shown to be a regulator in a large variety of cellular processes in multiple parts of the cell, including the nucleus, mitochondria, Golgi bodies, endoplasmic reticulum, cell membrane, and others.

Primarily, Cdc48 can serve such a large number of functions due to its ATPase activity. ATPase is an enzyme that jumpstarts a chemical reaction that decomposes adenosine triphosphate (ATP) â€“ the cellâ€™s energy currency â€“ into adenosine diphosphate (ADP) and a free phosphate ion. This energy release provides Cdc48 with the ability to change shape and also change proteins and other cell components around it. These changes lead to functions such as cell cycle regulation, protein degradation, and normal cell death.

How Does Cdc48 Contribute to Disease?

Cdc48 is the Swiss Army Knife of the cell because it can change shape and thereby change cell structures around it for functional purposes. However, it also could be termed the Swiss Army Knife of cell disease, as a single protein mutation can lead to multiple diseases. Since Cdc48 is able to interact with so many different molecules, a mutation of this protein is often pinpointed as the cause of disease.

For example, since Cdc48 has a role in genome maintenance and the expression of multiple different tumor suppressors, its mutation can lead to various cancers of the breast, ovaries, colon, lungs, liver, and pancreas. Similarly, due to its involvement in cell death, the normal degradation of proteins and the bodyâ€™s reabsorption of these cells, mutation of Cdc48 can lead to degenerative diseases like ALS, frontotemporal dementia, Charcot-Marie-Tooth disease, and Pagetâ€™s disease.

How Protein Unfolding Can Give Us Some Answers
Ever since the link between Cdc48 and this laundry list of diseases emerged, scientists have been searching for answers within Cdc48â€™s structure and functions. It is hoped that an understanding of how Cdc48 works can provide insight into how to treat and prevent the diseases it causes. Currently, the link between Cdc48 protein unfolding and its function are a key arena in which advancements could occur.

During this research, scientists purify and isolate the Cdc48 found in yeast cells, and take flash-frozen snapshots of the protein in its multiple configurations as it unfolds proteins. Using this method, scientists were able to demonstrate how Cdc48 threads proteins through its center and even identify the specific phosphatase complex it uses. Many scientists believe that the information found in this yeast Cdc48 research will translate directly to the same functions found within human cells.

More Research Is Needed

As research continues, providing the link between yeast and human Cdc48, more information will be revealed about how and why Cdc48 binds with so many partners simultaneously, and what mutations can mean for each binding relationship. Once the complete structure and relationships are clear, scientists can continue this groundbreaking work and begin to develop inhibitors and therapies for some of the most serious diseases involved.