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Scripps Research scientists solve mystery of nerve disease genes
Date:7/4/2011

inherit only one faulty copy of the GARS gene from one parent to get the disease.

The GARS gene holds the instructions for producing an enzyme called glycyl-tRNA synthase (GlyRS), which is vital to the process by which amino acids, the building blocks of proteins, are attached to one another during protein synthesis. So far, scientists have found 11 different kinds of mutations in the GARS gene that cause CMT type 2D. Some of the mutations affect the protein-building function of the GlyRS enzyme, but others don't, suggesting that a change in enzyme activity is not what causes CMT.

Thus, scientists have been trying to find a common feature shared by all GlyRS mutants that might explain the disease mechanism.

Structures in Solution

To find this common feature, Yang and colleagues turned to the three-dimensional structure of GlyRS. In 2007, they published the X-ray crystal structure of the wild-type protein and one of the mutants, but the structures were not all that different from each other (PNAS 104:11239-44, 2007).

"When we compared the wild type with the mutant, we did not find dramatic conformational change," said Weiwei He, a Scripps Research graduate student who joined Yang's lab and took on the project around the time of the 2007 paper's publication. "We thought maybe it was because of the crystal packing."

X-ray crystallography requires obtaining high amounts of a protein and packing the protein molecules into crystals that are bombarded with X-rays to determine the positions of all the atoms. This preparation, Yang and He reasoned, may mask any subtle conformation changes in a protein. "That is why we thought to look at the structure in solution, under more physiological conditions," said He.

In collaboration with Hui-Min Zhang, a postdoctoral fellow in the laboratory of Alan Marshall at the National High Magnetic Field Laboratory at Florida State University, Yang and He used a method to
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

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