One of the first things that students learn when they enter a biology class is the central dogma: DNA → messenger RNA → proteins.
Proteins are the workers of our cells. From signaling cascades to intracellular transport to energy metabolism to DNA repair, proteins are behind it all. In most introductory biology courses, we learn simply: Amino acids dictate a protein’s structure and thus determine its function as a result. However, there is another piece to this story — namely, what happens to proteins after they are formed. Post-translational modifications are chemical changes that can change a protein’s function, inactivate it or activate it.
Only about 3% of the human genome directly codes for proteins, which begs the question: What does all the other DNA do? That answer is long, complex and not completely answered, but it includes roles like gene expression regulation and post-translational modifications of proteins.
There are a huge number of different post-translational modifications — some of which have been historically harder to study than others such as glycation and ubiquitination. The Scheck Lab studies these modifications and develops chemical tools that can help us better understand them — both their mechanism of action and how they are regulated.
“We can think of [post-translational modifications] as part of a cellular vocabulary, so it’s the way that information is transmitted and shared in cells,” Rebecca Scheck explained.
Both glycation and ubiquitination present unique challenges when it comes to studying them. However, the Scheck Lab does not shy away from this complexity. Instead, the lab chooses to focus on these modifications that do not fit the norm.
“Most traditional tools focus on inhibiting the enzymes that put the modifications on or take them off, and we particularly focus on [post-translational modifications] that don’t fit that paradigm as well and just have some nuance,” Scheck said.
One such nuanced modification is ubiquitination, which is simply the addition of a ubiquitin protein to another protein (let’s call it the protein of interest). When ubiquitin is added to the protein of interest, the protein’s function is modified.
Ubiquitination is challenging because it involves three different types of proteins working together to install the modification: E1, E2 and E3. What makes this so complex is that there are around 40 E2 and over 600 E3 ligases — any combination of which can result in the ubiquitination of a protein.
With other modifications like phosphorylation, you just need to identify the one protein responsible for adding the modification, but with ubiquitination, distinct interactions must be identified. To do this, the Scheck Lab uses an approach to track interactions by illuminating the interactions of E2 proteins.
The other modification studied by the Scheck Lab is glycation. Glycation is a very unique post-translational modification because it involves sugars rather than proteins, and the mechanisms and situations when these modifications occur are not yet well understood.
The new tools that the Scheck Lab has developed have begun to reveal that there is a huge diversity within glycation. Scheck spoke a bit about one of the lab’s current hypotheses.
“One hypothesis we have in our lab right now is that maybe there’s two different types of glycation, and one is for this more longterm damage and the other could be some sort of faster acting dynamic [post-translational modification-like],” Scheck said. “We’ve been able to add a layer of chemical detail that’s allowed us to sort of tease out those two different ends of the spectrum.”
Developing tools to track these modifications can broaden our understanding of the processes they are involved in and the ways in which they are controlled, as well as perhaps even reveal further complexity in how post-translational modifications function.
While these projects are distinct, they have found fascinating ways to connect and feed off each other. For example, in one paper (currently in review), members of the Scheck Lab developed a method for studying glycation using ubiquitin. Due to the fact that ubiquitin itself is a protein, it too can experience glycation, and this new method studies glycation modifications on ubiquitin proteins. Post-translational modifications on post-translational modifications — now that’s pretty meta.
This research, while often super rewarding, is not without its challenges (but hey, nothing worthwhile is ever truly smooth sailing).
“You definitely have to be a little bit stubborn to be a good chemist,” said Jeremiah Jacob-Dolan, a fourth-year Ph.D. student in Scheck Lab.
This is especially true as the Scheck Lab, funded in part by National Institutes of Health grants, watches with much of the American scientific community as the future of scientific research is being threatened. But for now, research continues and with it come some very exciting new tools and discoveries that will help us continue to understand the intricacies and complexities of the world around us and the world within us.
