Biochemistry, Structural Biology
Memorial Sloan Kettering Cancer Center
Dr. Lima is also a member of the Structural Biology Program at the Memorial Sloan Kettering Cancer Center and a professor of biochemistry and structural biology at the Weill Cornell Graduate School of Medical Sciences and the Louis V. Gerstner, Jr. Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center.
Structure and Function in RNA Processing and Ubiquitin-like Protein Conjugation
In high school and college, artistic outlets like music and writing were so vital to Christopher Lima that he hesitated to commit to science: he thought it might not satisfy his creative side.
He need not have worried. "Most of the challenge of science," he says, "is coming up with more creative ways to solve a problem and brainstorm your way to a solution."
As a structural biologist, Lima has repeatedly exercised his ingenuity—and persistence—by using x-ray crystallography and biochemical techniques to reveal how proteins and nucleic acids in the cell communicate with each other. "We're trying to visualize these things at the atomic level: which atoms are touching other atoms," he explains.
Lima's major interest is the post-translational modification of proteins made by the cell. Newly minted proteins need further processing—folding, cutting, tagging with other proteins—to be ready to carry out their assigned functions and navigate to their designated place within the cell.
His group at Memorial Sloan Kettering Cancer Center focuses on how two small but important proteins, ubiquitin and SUMO (small ubiquitin-like protein modifier), attach to other proteins to redirect them within the cell or to modify their function. Ubiquitin and SUMO pathways are involved in differentiation, programmed cell death, the cell cycle, and stress responses. "Ubiquitin and SUMO pathways are essential for many different processes and are conserved from yeast to humans," Lima says. Disruptions in these pathways underlie some neurodegenerative diseases and cancers.
SUMO proteins regulate their target proteins through a series of reactions involving enzymes known as E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. The E1 enzyme is the Achilles' heel of the pathway—block E1 activity and the entire pathway shuts down. "We've been interested in trying to understand how E1 works so we could potentially design inhibitors," Lima says. The aim is to slow down excessive cell proliferation in diseases like cancer.
Lima has made a series of key discoveries about SUMO's lifecycle—how SUMO is activated, how it is attached to and detached from proteins, and how it recognizes various proteins. Planning and carrying out these difficult experiments demand the creativity he prizes.
"A lot of the most interesting things are those that occur transiently, in extremely short-lived chemical reactions involving intermediates that are quite unstable," explains Lima. "So you have to use a lot of tricks to trap the intermediates. Sometimes you have to guess what the intermediates should look like and then make analogs using structure-based drug design." Then you test the hypothesis.
"There are lots of proteins that we know are modified by SUMO, but we have no idea what they do," he says. "Our research aims to understand how these modifications change behavior of particular proteins and the proteins with which they interact."
In another area of interest, the Lima group solved the structure of the RNA exosome, a key enzyme involved in RNA decay and quality control. For example, it destroys messenger RNAs that contain errors.
"We took on this problem with the RNA exosome before anyone thought it could be done," Lima says. Ultimately, the researchers expressed 11 protein subunits of the yeast RNA exosome and reconstituted it to determine its activities. They also determined the crystal structure of the nine-subunit human RNA exosome. This advance will help scientists determine the functions of the exosome, which among other things is involved in certain neurodegenerative and autoimmune diseases, as well as the response of cancer cells to certain treatments.