Active region of enzyme tied to stuttering identified

Scientists led by an Indian-origin researcher have determined the 3-D structure of the chemically active part of an enzyme involved in stuttering.
While the discovery is not likely to lead to a cure for stuttering any time soon, it is welcome news to scientists who have been studying this enzyme, known as "uncovering enzyme" or UCE, for decades.
Not only does UCE play a role in the type of persistent stuttering that is passed down in families, but it's also an important part of the system that breaks down and recycles unwanted molecules in our cells.
Knowing its 3-D structure will aid studies of all these systems, and of the health problems that result when they malfunction.

Scientists from the Joint Center for Structural Genomics (JCSG) at SLAC National Accelerator Laboratory led by Debanu Das reported the finding in the Journal of Biological Chemistry.
Das is a structural biologist and protein crystallographer at SSRL, the Stanford Synchrotron Radiation Lightsource, and a member of the JCSG, a multi-institute consortium that rapidly screens proteins coming out of gene mapping projects to determine their structure and function.

At SSRL, researchers aim powerful X-ray beams at crystallised samples of protein, creating patterns that reveal the protein's 3-D structure.
In this case, Das and his colleagues were working on the structure of DUF2233, a protein taken from one of the microbes that inhabit the human gut.

Scanning protein databases and scientific reports, they learned that members of this new protein family were found in thousands of bacteria and in some viruses, but had only one representative in humans - UCE.
"The microbe and human forms were not identical, but they were obviously related," Das said.
Three years ago, researchers discovered that three mutations in UCE itself were linked to persistent stuttering that is passed down in families. It is thought, but not yet proven, that these mutations may impair the functioning of critical neurons involved in speech.
Das collaborated with Stuart Kornfeld, a hematologist at Washington University School of Medicine in St Louis, and working from the structure of microbial DUF2233, Das created a computer model that predicted the structure of the same region in human UCE.

It showed a cavity on the surface of UCE that appears to be the 'active site' where the enzyme brings other chemicals together and induces them to react with each other, a process known as catalysis.
With that model in hand, Kornfeld and other collaborators created various mutations in UCE to see what effect they had on the enzyme's function. These experiments verified that Das had indeed identified the enzyme's active site.