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.

Public Health Relevance

The overall objective of this research is to define in structural and physical terms the molecular mechanisms that regulate protein tyrosine kinase (PTK) function. Because PTKs regulate signal transduction processes that are essential in all aspects of cell growth, differentiation, metabolism, and programmed cell death, abnormal regulation of PTKs is associated with numerous diseases. A trait of most protein kinases is that tyrosine phosphorylation controls their function, in particular their recognition for various cellular binding partners and their structural plasticity. The proposed research aims to elucidate mechanisms of this control for Syk and Src PTKs with the goal of contributing new knowledge that is useful in fighting human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Flicker, Paula F
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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Feng, Chao; Roy, Amitava; Post, Carol Beth (2018) Entropic allostery dominates the phosphorylation-dependent regulation of Syk tyrosine kinase release from immunoreceptor tyrosine-based activation motifs. Protein Sci 27:1780-1796
Wu, Heng; Post, Carol Beth (2018) Protein Conformational Transitions from All-Atom Adaptively Biased Path Optimization. J Chem Theory Comput 14:5372-5382
Mo, Huaping; Harwood, John S; Yang, Danzhou et al. (2017) A simple method for NMR t1 noise suppression. J Magn Reson 276:43-50
Post, Carol Beth; Levy, Ronald M (2017) Editorial overview: Theory & computation. Curr Opin Struct Biol 43:iv-vi
Skeel, Robert D; Zhao, Ruijun; Post, Carol Beth (2017) A minimization principle for transition paths of maximum flux for collective variables. Theor Chem Acc 136:
Feng, Chao; Post, Carol Beth (2016) Insights into the allosteric regulation of Syk association with receptor ITAM, a multi-state equilibrium. Phys Chem Chem Phys 18:5807-18
Roy, Amitava; Hua, Duy P; Post, Carol Beth (2016) Analysis of Multidomain Protein Dynamics. J Chem Theory Comput 12:274-80
Hua, Duy P; Huang, He; Roy, Amitava et al. (2016) Evaluating the dynamics and electrostatic interactions of folded proteins in implicit solvents. Protein Sci 25:204-18
Ysselstein, Daniel; Joshi, Mehul; Mishra, Vartika et al. (2015) Effects of impaired membrane interactions on ?-synuclein aggregation and neurotoxicity. Neurobiol Dis 79:150-63
Roy, Amitava; Hua, Duy P; Ward, Joshua M et al. (2014) Relative Binding Enthalpies from Molecular Dynamics Simulations Using a Direct Method. J Chem Theory Comput 10:2759-2768

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