Protein’s ‘hopping’ behavior uncovers new drug development avenues

Since 2006, Ruben Gonzalez’s Columbia lab has used single-molecule light microscopy to study the structural dynamics of biomolecules.

In lay person’s terms, that means: they use hyper-powerful microscopes that generate movies of what individual molecules look like as they perform the actions that make our bodies tick.

Gonzalez is a professor of biophysical chemistry in Columbia’s Faculty of Arts and Sciences and at the Columbia University Irving Medical Center, and will become Dean of Science in the Faculty of Arts and Sciences in January.

In a new paper out this month in the journal Nature, he and his lab describe a major new finding about how the eIF4F protein interacts with messenger RNAs. Columbia News spoke with Gonzalez about his research, and how his latest finding could affect drug treatments for diseases like cancer.

Can you explain your lab’s work broadly?

My lab is interested in trying to understand how the motions of biomolecules—molecules produced by the body—contribute to their functions. We record movies to give us a data-informed sense of what those motions look like. That allows us to understand how the biology really functions, which in turn can help us and other scientists think about how we might control that biology by manipulating such motions, providing a new paradigm for developing therapies to tackle diseases like cancer.

There are many cases where drugs act by impairing a biomolecular motion, so understanding that motion is crucial.

The dream is to be able to record these movies at atomic scales and in real-time. But we’re not there yet.

What led you to record these movies?

For a long time, static images of biomolecules at atomic scales exhibited blurry regions, which led scientists to the conclusion that parts of the biomolecule were moving, and that such motions might be important to biology. It sort of captured my imagination. What are the moving parts, and where are they moving? What is the timing of these motions, and why is all of this important? Those kinds of questions have really been the driving feature of all we do in the lab.

We do a lot of technology development in my lab. We build these microscopes, we optimize them, we continuously push the technology. We also have a whole group that develops computational algorithms and software for the analysis of the data that comes from these.

What does the new paper in Nature show?

To make proteins, which are the building blocks of everything in our cells and in our bodies, cells need to prepare messenger RNAs (mRNAs), the molecules that carry the building instructions. They do that with the help of a protein called eukaryotic initiation factor 4F, or eIF4F, that must converge at a certain location at one end of the mRNA, which we call the mRNA “cap.”

Using our movie technology and led by graduate students Riley Gentry and Nicholas Ide, we discovered—quite unexpectedly—that eIF4F doesn’t just directly assemble at the cap as everyone had always assumed. Instead, it ‘hops’ along the mRNA trying to identify the cap.

One reason this is important is that drugs, such as anticancer drugs, that aim to disrupt this process in order to stop dangerous cells like cancer cells from proliferating currently target the direct assembly of eIF4F at the cap. Our finding provides a deeper understanding of how eIF4F actually finds its way to the cap on the mRNA, which will help us develop more targeted therapies for cancer and other diseases.

What makes the finding significant?

There are a number of things that make this a significant finding. It’s really redefining something fundamental about this critical biological function, in a way that will rewrite what’s in textbooks. It also answers some big, decades-old questions that we and others have had, which is that we’ve known for decades that different regions and properties of the mRNA that are far away from the cap can influence the ability of eIF4F to converge at the cap, but no one has ever been able to figure out how that could be, and our findings help explain this.

Another reason is that if you can develop drugs that influence the search that eIF4F does along the mRNA, it could have big implications. It could help us more precisely target particular mRNAs, manipulating the production of the specific proteins at the heart of the disease. That could mean that future cancer drugs would use something more like a scalpel than a sledgehammer to stop molecular motions that have gone awry, rather than halting a whole bunch of processes that include the dangerous ones you want to stop but also good ones you would want to leave unimpaired.