Emory scientists discover unique binding method for essential cellular protein ubiquitin

New information on ubiquitin pathway could lead to possible drug development

Researchers at Emory University School of Medicine have uncovered new information about the molecular pathway used by ubiquitin, an essential protein that helps regulate the amounts and locations of other proteins within cells. Because ubiquitin plays a key role in cell survival, scientists have already begun to develop drugs to target parts of the ubiquitin pathway in treating diseases such as cancer.

Emory biochemist Keith Wilkinson, PhD, senior author of the study published in the March 23 issue of Cell, has been investigating ubiquitin since the late 1970s, when he was a research fellow in the laboratory of Irwin Rose, one of three scientists awarded the 2004 Nobel Prize in Chemistry for the discovery of how ubiquitin degrades proteins within cells.

In the current study, Dr. Wilkinson and first author Francisca Reyes-Turcu, graduate student, report for the first time on how ubiquitin binds to Isopeptidase T (IsoT) an enzyme responsible for disassembling chains of ubiquitin. Since the initial research on ubiquitin, scientists have understood that chains of ubiquitin direct proteins to the proteasome (a structure inside cells that breaks down protein) for degrading when they no longer are important to the functioning of the cell. "When the protein has been targeted with the ubiquitin chain to go to the proteasome, the protein gets degraded," explains Ms. Reyes-Turcu, a graduate student in Emory's Graduate Division of Biological and Biomedical Sciences.

The Emory scientists focused on IsoT because of its pivotal role in degrading, recovering and reusing ubiquitin from ubiquitin chains. "Although scientists knew that IsoT had an essential role in the recycling of ubiquitin, the structure of IsoT and how it recognized and bound to ubiquitin was not understood," said Ms. Reyes-Turcu.

Ms. Reyes-Turcu decided to focus on one area of IsoT called the "zinc finger domain," which consists of amino acid residue held together by a zinc ion. Using x-ray crystallography--a technique for imaging on the molecular level--she provided the first images showing that a ubiquitin chain binds to IsoT by inserting one end of a chain into a pocket on the zinc finger domain.

"Most of biology is driven by two proteins interacting in some way," Dr. Wilkinson notes. "The original idea was that these interactions were like a lock and a key, with shapes that were completely complementary and just fit together. This concept has been refined as people have realized that both molecules can breathe and move."

The zinc finger domain is the first structure of this class of domains to be crystallized and imaged. Because it is present in other ubiquitin-binding proteins, proteins similar to IsoT may also employ a pocket for binding to ubiquitin chains. Says Ms. Reyes-Turcu, "This domain is present in other proteins, so it raises the question that other proteins might recognize ubiquitin in the same way."

If she is correct, proteins such as BRAP2/IMP, which interacts with BRCA1, a protein implicated in breast and ovarian cancer, could soon be up against pharmaceutical treatments targeting the same zinc finger pockets. Dr. Wilkinson adds, "The knowledge that we gain from the zinc finger structure could allow us to design a drug to occupy that pocket and modulate the activity of the ubiquitin pathway to treat certain diseases."

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The study was funded by the National Institutes of Health and the American Heart Association.


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