What is the research focus of the Zurita-Lopez laboratory? Arginine Methylation.
In auto racing, cars stop and get serviced by a pit crew. For example, in the photo shown here, a pit crew is refueling and adjusting a race car. A pit crew member might change a tire in order to improve the performance of the race car. Since a pit crew has only 10 seconds, they must coordinate with each other. They have to work quickly and accurately so that the car can hurry up and get back in the race!
Everything about this pit stop is well orchestrated. The stop itself is strategically timed, accounting for rate of fuel consumption, weight of fuel and even the weather and lighting conditions! In the photo, you can see that the pit crew members each have separate jobs. Some might seem minor, but all work together to help the car win the race.
What would happen if the pit crew is not well coordinated? If each of the crew members fought over a particular part of the race car? What if the pit stop wasn't even planned?
Diseases first begin with small changes at the molecular level. Just like a pit crew, we have proteins (enzymes) that modify other proteins in our cells. These modifications must be well executed for proper cellular function.
In a healthy person, the modification serves to signal proper function. However, sometimes, a mistake in these modfications will lead to greater errors. When this happens, proteins fail to function properly and in turn unleash a cascade of effects that ultimately leads to diseases.
Is it possible to detect diseases as soon as changes occur at the molecular level? Before painful symptoms arise. Before the disease becomes widespread? To do this, we must first understand the early molecular changes that occur inside cells. We must first understand these initial modifications of proteins and their meaning.
Arginine methylation is one type of protein modification implicated in many cellular processes and correlated with diseases such as multiple schlerosis, lupus and diabetes.
Our research focuses on arginine methylation.
Posttranslational modifications (PTMs) describe a change that occurs after protein synthesis. While there are many types of PTMs, including phosphorylation, acetylation, ubiquitination, sumoylation and neddylation, we are particularly interested in understanding the role of arginine methylation, the addition of a methyl group onto the arginine residues in proteins.
The enzymatic addition of a methyl group to arginine residues in proteins is essential to our overall knowledge of cellular biochemistry and physiological function. The enzymes responsible for arginine methylation, protein arginine methyltransferases (PRMTs), have been found in nearly all eukaryotic organisms including protozoa, fungi, flies, plants and animals. To date, there are nine confirmed human methyltransferases, PRMT1-9.
Protein arginine methylation was initially observed in 1967. Since then, many arginine-methylated proteins or substrates have been discovered. These include estrogen receptor alpha (ER-α), the transcription factor and tumor suppressor protein p53, spliceosomal proteins (i.e. SMN, snRNPs) and the DNA repair protein MRE11. PRMTs also methylate histone proteins. Thus, like phosphorylation, methylation affects regulatory mechanisms in the cell and is now implicated in a variety of diseases including cancer, lupus and diabetes.
Does arginine methylation block neighboring phosphorylation?
In cells, information is transmitted via signal transduction by phosphorylation cascades that are misregulated in many diseases. To ensure efficient and accurate cell signaling, kinases, the enzymes responsible for phosphorylation, must first recognize a specific signal sequence or motif on a protein. One such motif is known as the Akt motif. Studies have shown that protein arginine methyltransferases methylate arginine and that this modification blocks serine phosphorylation (Figure 2). It is our hypothesis that there are many motifs like the Akt motif, whose phosphorylation can be modulated by methylation. Testing the limits of these phosphorylation motifs as they respond to arginine methylation will provide a complete catalogue of validated methylation/phosphorylation crosstalk substrates, thereby aiding in deciphering the molecular codes by which proper cell signaling occurs.
Our laboratory is currently investigating crosstalk in two proteins: histone H3, a protein that is implicated in cancer and PGC-1alpha, a protein implicated in metabolism and obesity. We propose that arginine methylation can inhibit phosphorylation of neighboring serine residues in these proteins regardless of the kinase phosphorylating the substrate. This work is fundamental to understanding the effects of crosstalk between posttranslational modifications (PTMs) and protein regulation. In addition, abnormal phosphorylation is a cause of many diseases. This work will aid in providing a novel approach to regulating phosphorylation and can potentially serve as a novel therapeutic target.
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