UWindsor biochemistry graduate student Cody Caba and professor Bulent Mutus display the crystal structure of protein disulfide isomerase. Mutus received an NSERC Discovery Grant to examine cell proteins and structures and how they contribute to diseases.
Bulent Mutus is a micro mechanic.
But instead of fixing cars with wrenches and grease, the biochemist rolls up his sleeves and chops up and rebuilds proteins using microscopes and Petri dishes.
“If this enzyme were a car we would know where the engine is, but now we are looking at turning that engine off so the pathology will go away,” the UWindsor professor said.
Dr. Mutus recently received a $100,000 Discovery Grant over five years from the Natural Sciences and Engineering Research Council of Canada (NSERC) to examine cell proteins and structures and how they contribute to diseases like cystic fibrosis and Alzheimer’s.
The human body is made up of about 10 trillion cells that intricately interact with one another to ensure the body functions properly. When cell-to-cell and internal cell signaling is disturbed, the body cannot function properly, and acute diseases and physiological or neurological disorders occur.
“It’s similar to a teeter-totter, wherein a normal situation everything is balanced,” Mutus explained.
Every cell contains strings of amino acid molecules that fold onto themselves, forming structures called proteins.
The crystal structure of protein disulfide isomerase is pictured in this computer visualization.
“If there’s something that messes up the balance within the cell, then the proteins don’t fold properly, and you get something called unfolded protein response,” he said.
Diseases reactive to the unfolded protein response include Alzheimer’s, Parkinson’s and Huntington’s — as well as many others.
Proteins are encoded from DNA instructions and form in ways that allow them to combine with other substrates to perform work. When proteins do work, they are called enzymes and help the body to function properly.
Mutus’ NSERC research focuses on a sequence of amino acids containing sulfur, called cysteine amino acids, and the role they play in the regulation of enzymes. In the sequence, called the CXXC motif, two amino acids represented by the letter C for cysteine, are separated by any other two of the 23 amino acids, which are represented by X. These cysteine amino acids have a sulfur group that often binds to itself to create a stronger bond or fold within the protein structure.
Mutus said the sequence affects structure which in turn affects the function, and so improper sequences or structures can cause harmful pathologies in the body.
“Structure is related to function, and so if you build a building and you don’t have any doors it’s not going to be very functional,” the researcher said. “The same goes with a protein, and if a sequence works well in one particular protein, then it’s copied and repeatedly used somewhere else.”
By studying this CXXC protein sequence and its function in various cellular pathways, researchers can develop therapies to treat diseases caused by improper function.
Mutus’ lab has created probes that will bind to CXXC enzymes within the cells which can be followed to see their functions in internal cellular pathways.
He said an example of this is found in patients with cystic fibrosis. Within these patients, an enzyme called S-Nitrosoglutathione Reductase (GSNOR) is unable to form at appropriate levels in the lungs and can’t function in ion transport.
“If that ion transport protein can’t mature and enter into the cell membrane where it belongs, then fluid essentially starts to accumulate in the lungs and leads to infections,” Mutus said. “So if an enzyme contains this CXXC motif, and we think we can tweak onto something that’s a very small run of four or five amino acids, where we can play with one of the amino acids and really regulate the enzyme, like turning a car engine on and off to control negative pathologies in the body.”
Mutus’ research will eventually have implications in drug design as a means of controlling these important enzymes involved in pathologies and diseases that may affect all of us.
See the full story at the UWindsor Daily News