Molecular mechanisms of Bcl10-mediated NF-kappaB signal transduction /

by Langel, Felicia D

Title: Molecular Mechanisms of Bcl10-Mediated NF-kappaB Signal Transduction Author: Felicia D. Langel, Ph.D., 2006 Directed by: Brian C. Schaefer, Ph.D., Assistant Professor, Department of Microbiology and Immunology Bcl10 is a key signaling intermediate in the TCR-to-NF-?B pathway in T lymphocytes. It is currently believed that, once activated, Bcl10 functions within a multiprotein signaling complex that activates the IKK complex. Bcl10 is thought to regulate this signaling complex, but how it transmits its signal through the complex is unknown. A thorough knowledge of Bcl10 biology is critical to understanding how Bcl10 functions and how it regulates its binding partners. In this study, we used mutational analysis, molecular imaging, biochemistry, and computer/bioinformatics modeling to elucidate a structure and function for Bcl10. From our data, we identified a novel binding site for MALT1 within the Bcl10 protein, hypothesized that this site is completely separate and distinct from the binding sites of other Bcl10 signaling partners, and proposed two regulatory functions for the Bcl10 C-terminus. These findings suggest that Bcl10 has multiple functional domains and, hence, that Bcl10 molecular biology is more complex than previously thought. These observations serve to emphasize Bcl10’s role as a crucial regulator of the TCR-to-NF-?B signaling pathway. i