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Structural Motif in Key Enzymes Is Essential to Prevent Autoimmune Disease

By Drug Discovery Trends Editor | January 16, 2009

Scientists from The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF) have found a specific mutation that leads to the development of severe autoimmune kidney disease in mice. The research sheds light on the basic biology of the immune system, as well as on the effectiveness of drugs such as the anti-leukemia medication Gleevec/Imatinib.

In the study, the scientists identify a disease-causing mutation in a binding structure common to dozens of kinases—specific enzymes, especially important in cell signaling, that can modify other proteins by transferring a phosphate group onto them. The mutation reduced the activity of an important kinase, Lyn.

‘Our study has several important implications,’ said Karsten Sauer, a Scripps Research scientist and assistant professor who led the study. ‘First, it shows that when you eliminate the activity of the Lyn kinase through mutation, you develop problems in B cell signaling, resulting in B cell hyperactivity which leads to a severe autoimmune reaction—in this case, autoimmune glomerulonephritis, a form of kidney disease very similar to human lupus. This shows for first time how essential the Lyn kinase activity, and not potential adaptor or scaffold functions of the protein, is for B cell signaling, and for preventing autoimmune disease.’

B cells produce pathogen-fighting antibodies and are a critical part of the adaptive immune system.

The study showed that, in so-called ‘WeeB’mice, mutational disruption of a binding structure results in expression of a Lyn protein with reduced catalytic activity and disturbed B cell receptor signaling. These mice show profound defects in B cell development and function and quickly succumb to the kidney disease.

The structure in which the mutation occurs, called a G-loop, allows for the process of adenosine triphosphate (ATP) binding—the cell’s main energy source—and phosphate transfer in the protein kinases. The structure also controls the binding of ATP competitive compounds, such as Imatinib (Gleevec), the chronic myeloid leukemia (CML) treatment that is the first approved drug targeting another kinase, Abl, in rapidly dividing cancer cells.

The WeeB mutation disrupts a molecular bridge within the Lyn G-loop that, Sauer and colleagues found, stabilizes the structure, limiting its inherent flexibility, and contributes to proper ATP binding and the transfer of the phosphate group during catalysis.

Release Date: January 15, 2009
Source: The Scripps Research Institute


Filed Under: Genomics/Proteomics

 

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