CSHL’s Joshua-Tor solves mysteries by studying structure

CSHL’s Joshua-Tor solves mysteries by studying structure

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Hollywood came to Leemor Joshua-Tor’s lab. When actress Rachel Weisz was preparing for her role as a scientist in “The Bourne Legacy,” she and director Tony Gilroy visited Joshua-Tor’s lab at Cold Spring Harbor Laboratory.

Like Weisz’s aunt, Olga Kennard, Joshua-Tor explores the unknown structure of complex molecules. While she may not have a Hollywood pedigree, Joshua-Tor has had a hit of her own, thanks to her research on a protein linked to an important function in biology.

A professor at Cold Spring Harbor Laboratory and an investigator at Howard Hughes Medical Institute, Joshua-Tor was one of many scientists seeking to understand how a gene-regulating mechanism worked. Through a process called RNA interference, a small RNA molecule either enters the cell or is produced from long RNAs in the cell and is cut to pieces. That small piece sticks to an RNA that is normally part of the process of converting DNA to proteins. Once that RNA gets cut, the genetic machinery comes to a stop.

While researchers knew there was a collection of proteins in the silencing signal, they weren’t sure which one was helping to hit the stop button or how that protein might work. A structural biologist, Joshua-Tor took a different approach. She figured she might be able to find the important protein by looking at molecular architecture. What she found was that the small RNA sticks to the Argonaute protein and then “seeks” the larger RNA.

Steve Harrison, a professor at Harvard Medical School and an investigator with the Howard Hughes Medical Institute, called Joshua-Tor’s 2004 discovery of Argonaute’s role an “important contribution. It is a key step for understanding the biochemistry of small RNA-guided gene regulation.”

Joshua-Tor explained that being able to see the molecules provides a better understanding of what is happening and, perhaps, how.

“All RNA interference processes included the Argonaute protein, but no one knew what it did,” she recalled. The protein is “at the heart of the execution phase” of interference.

RNA interference can protect cells against viruses, while it can also help monitor and regulate gene expression.

While the Argonaute protein carries out many processes, it works through other proteins as well, Joshua-Tor said. It plays a role as a tumor suppressor in prostate cancer.

In addition to the work her nine-person lab does on Argonaute, Joshua-Tor’s team is also looking at proteins that are involved in papilloma viruses. These viruses, which can cause benign or malignant tumors in areas like the cervix, use an initiator protein, called E1. Together with a former postdoctoral student, Eric Enermark, who now works at St. Jude Children’s Research Hospital and in collaboration with CSHL’s Arne Stenlund, they discovered how E1 recognizes and binds the start site. Enermark and Joshua-Tor later figured out how the protein uses the energy of adenosine triphosphate to travel on the DNA.

While structural biology involves numerous steps to go from targeting a molecule to seeing how all the parts fit together, the effort can create “an amazing feeling. You put up with a lot of grief in order to relive that rush when you see a structure for the first time. It’s just unbelievable,” Joshua-Tor said.

A resident of Huntington, Joshua-Tor lives with her five-year-old daughter Avery. The mother-daughter team enjoy going to beaches and visiting the Long Island Aquarium and Exhibition Center in Riverhead. Avery also “loves playing with the kids on our block,” which includes an annual fall block party, which has a deejay, races, water-balloon competition and scarecrow making.

Joshua-Tor, who spent part of her childhood in Israel and attended high school in Great Neck during her junior year, also enjoys the wineries and the “amazing” fresh corn of the east end.

Joshua-Tor said she loves the history of science and finds herself thinking about earlier discoveries that used the same technique, X-ray crystallography, that she employs in some of her research.

“Molecular biology is riddled with discoveries in structural biology,” she said, including by researchers like Dorothy Hodgkin, who confirmed the structure of penicillin and of vitamin B12, which helped her win the Nobel Prize in Chemistry in 1964. “We stand on the shoulders of our predecessors.”