NMR Structure of peptide and protein complexes

Purdue University, West Lafayette IN

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand in terms of structure and dynamics the molecular mechanisms that regulate Syk and Src tyrosine kinase function in cellular signal transduction. A vast number of human diseases are linked to improper functioning of protein tyrosine kinases, and inhibitors of Src kinase are in clinical use. A trait of most signaling proteins is their engagement with multiple binding partners for the purpose of controlling cellular localization and enzymatic activity. This ability to form a variety of protein-protein interactions requires conformational flexibility, and thus characterization of this flexibility and diversity is a basic component of understanding, and eventually predicting, these molecular recognition events. To this end, solution NMR and computational methods will be used to investigate four aims related to conformational transitions and molecular recognition of Syk and Src-family protein tyrosine kinases in the context of B cell signaling. Syk association with other signaling proteins is regulated by tyrosine phosphorylation within the linker regions interdomain A (IA) and interdomain B (IB). (1) The hypothesis that the dissociation of Syk from the B cell receptor is triggered by structural disorder induced at a distance by phosphorylation of IA will be tested. (2) The structural basis for recognition of alternative patterns of phosphorylation of IB at two closely spaced tyrosines by various downstream effector proteins will be determined. Src kinases phosphorylate the B cell receptor which then forms the binding site for Syk to initiate intracellular signaling. (3) Activation of Src kinases is well known to require conformational change but the details of the transition pathway are unknown and will be investigated. (4) The receptor substrate interactions of Src kinase are will also be determined.