Imagine the inside of a cell is like a bustling city where a variety of projects are underway, such as building bridges, erecting skyscrapers and paving roads. In order to build and complete their projects, each different construction team member needs to find each other and coordinate their efforts and the placement of the building materials to complete their projects, despite the chaos of constant movement and noise all around them.

The same thing happens in our cells every day all day long. All cells in our body rely on building and using large assembled complexes (called assemblies) made up of multiple parts to carry out essential processes to function and survive. Understanding how these multi-subunit complexes are built inside our cells will provide important information about cellular biology that can be applied across many living organisms, including humans.

Dr. Michael McMurray is a scientist who runs a research lab on the University of Colorado Anschutz Medical Campus in Aurora. His research team studies how large protein structures made of multiple parts are built and come together inside cells. Most of their recent work has focused on proteins called septins. Septins play a role in many important functions within our cells; they provide structure and assist in cell division and cell movement. While scientists have studied the final shapes of these septin clusters in detail after they’ve been built (like examining a skyscraper after it has been built), they still don’t fully understand how the individual parts find each other and fit together during the building process in the busy and constantly changing environment within a cell. The McMurray lab thinks the lessons they learn about how septins assemble will also apply to assemblies made of other proteins.

Michael and his team use yeast to study the assembly of multicomponent structures within cells.

To explore this area of cell biology research, the McMurray lab uses budding yeast (Saccharomyces cerevisiae) as their model organism to study because it is a very powerful tool in scientific research laboratories for many different purposes. In fact, septin proteins were first discovered in budding yeast! In the McMurray lab the speedy growth of budding yeast cultures and the many reagents available to study yeast proteins are used to carefully investigate how septin proteins are built and function during yeast cell division. Since every cell division produces two cells from one cell, this is a time of life when yeast need to make and assemble new proteins to make new cells.

Using yeast as a model system for this research study allows Michael and his research team to figure out how these multi-subunit septin complexes are built. They will then use this information to better understand what can go wrong during the septin assembly process and how defects in human septin assembly appear to be linked to diseases, such as cancer, male infertility, and Alzheimer’s disease. Years of cell and developmental biology research have shown us that proper cell structure, organization and division are critical to maintain the health and integrity of every cell as well as the health and integrity of entire organisms – even humans!

What experiments do Michael and his researchers do to answer their questions?

The McMurray lab makes new strains of yeast to introduce changes that allow the research team to “see” interactions between the septin proteins inside the cells. Often, detecting the interactions between proteins inside cells involves using high-powered microscopes and molecules – called fluorescent proteins – that light up and glow when light from a microscope shines on them. In other cases, the yeast cells can be made to live or die depending on if two septin proteins bind each other. Yeast cells are used for many reasons in the McMurray lab. They are easy to use, inexpensive, and grow quickly!  Using yeast cells for their research means that the lab can perform many different experiments at the same time and get results within a few days or even hours.

Yeast to the rescue! Exciting discoveries that could lead to treatments for human disease

Some recent McMurray lab yeast studies have already discovered how septin assemblies form in human cells. In budding yeast, each septin complex is always built from exactly eight septin proteins, but it was known that human cells also make six-subunit septin complexes. The McMurray lab discovered that the difference between yeast and human cells is that one of the human septin proteins can make two different kinds of interactions, like a support bracket in a skyscraper’s scaffold that can make either a two-way or a three-way junction. During evolution, the equivalent septin protein in yeast changed its shape and lost the ability to make the kind of interaction that allows six-subunit complexes to form.

An unexpected discovery ––which happens surprisingly often in research–– was made by the McMurray research team; they found out that a simple molecule  – called guanidine hydrochloride – can bind to the yeast septin protein and restore its ability to make six-subunit septin complexes! It turns out that guanidine occurs naturally inside the cells of some organisms, and the McMurray lab found other examples in which guanidine or other naturally occurring small molecules can bind to proteins in living cells and change their shapes. In some cases, the small molecule could restore normal function to a mutant protein allowing it to work again.

Regarding the connection between this research and human disease, it is known that some of these mutations can cause human disease. Because of the research in the McMurray lab and other scientific discoveries, some of these small molecules that are already approved by the FDA for use in humans could be repurposed to help treat certain diseases. This unexpected discovery studying septin proteins in yeast may have provided new clues to potential therapies for genetic diseases in humans!

Future Directions for this research...

Dr. McMurray and his research team will continue to investigate how septin assemblies are built and function in yeast cells and how small molecules (like guanidine) might contribute to restoring function.

If you want to learn more about the scientist, please head to their official CU webpage. 

Michael McMurray CU webpage link: https://medschool.cuanschutz.edu/cell-and-developmental-biology/faculty/michael-mcmurray