Kinase mediated tyrosine phosphorylation is a crucial component of cellular signaling cascades. Precise regulatory control over kinase activity must be maintained during signaling as evidenced by numerous human diseases that arise upon dysregulation of protein kinases. Given the crucial role of kinases in cell signaling, these enzymes are key targets in treating disease. Traditional approaches for therapeutic targeting of kinases have involved small molecules that exert their effect directly on the kinase active site. The increasing instances of resistance to such drugs suggest a need for devising new ways to target kinase activity. One way to accomplish this goal is to better understand the structural features of specific kinases as they transition between autoinhibited to activated states. In our work on the Tec family tyrosine kinases (immunological kinases involved in signaling downstream of antigen receptors), we have identified a completely new structural form of Bruton?s tyrosine kinase (BTK); an enzyme required for B cell development and function. The current application lays out aims to fully characterize the multimerized BTK structure observed by single particle electron microscopy. To carry out the proposed work we have established strong collaborations with Dipali Sashital at ISU and Bridget Carragher & Clint Potter at the National Resource for Automated Molecular Microscopy (NRAMM). We anticipate that successful completion of the proposed studies will not only open new avenues to target BTK but will also add to the growing understanding of the role of higher order complexes that control B cell signaling.
This proposal is to fully characterize a newly discovered structural conformation of the immunological kinase BTK. After decades of intense study, we have now identified a specific BTK multimer structure that likely is an important component of the B cell?s ability to respond to pathogens. The public health relevance of the project relates to developing new ways to either limit or enhance the immune response in the face of autoimmunity, immunosuppression or immunoproliferative diseases.
