Functional Studies of Erythrocyte Dematin

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Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. It is well recognized that the "spectrin-actin junctions" are functionally essential for the maintenance of erythrocyte membrane stability and mechanical properties. The prevailing paradigm is that these junctions are linked to the plasma membrane via an interaction between protein 4.1 and glycophorin C. Our current model predicts that dematin, in conjunction with adducin, assembles a novel cytoskeletal complex at the tail ends of spectrin polypeptides that link these junctions to the plasma membrane. In this competitive renewal application, we will use the following experimental approaches to validate our hypothesis: Combined deletion of mouse dematin and adducin results in severe anemia with highly fragile erythrocytes. To elucidate the mechanism of weakened spectrin-actin linkage to the plasma membrane, we will investigate the status of actin protofilaments, rescue membrane instability defect, examine the effect of double mutation on known vertical interactions, and test direct binding of dematin with adducin and its regulation by phosphorylation and oligomerization. Importantly, we will use the double knockout mice that completely lack dematin and beta adducin to investigate whether the residual core domain of dematin exerts a dominant negative on the stability of the erythrocyte membrane. Since dematin and adducin are widely expressed, including the platelets and heart muscle, the proposed studies are potentially significant for understanding the molecular basis of cardiovascular diseases such as hemolytic anemia and related bleeding disorders.