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Abstract
Tyrosine kinases are regulated through diverse mechanisms that control enzymatic outputs based on the presence of specific molecular cues. The biomedical relevance of tyrosine kinases has driven extensive research on a number of tyrosine kinases such as Src and the oncogene epidermal growth factor receptor, however, regulatory mechanisms in many other tyrosine kinases still remain unknown. In this work I apply rigorous, large scale sequence comparisons to study the evolution of tyrosine kinases. First, I determine a new hierarchical classification of the tyrosine kinome, which reflects the modular evolution of distinct and anciently conserved regulatory cores. Next, I use computational and experimental approaches to demonstrate how sequence features unique to the Ephrin family of tyrosine kinases contribute to an allosteric coupling between the juxtamembrane and sterile motif linker to uniquely regulate the activation of Ephrin kinases. Last, through a comprehensive analysis of pseudokinase sequences, I propose a new classification of pseudokinases families that reflects their evolution from diverse canonical kinases and through the selection of sequence motifs that stabilize unique inactive kinase domain conformations and contribute to other non-enzymatic functions. The findings presented here shed light on how diverse functions and regulatory mechanisms have evolved in the tyrosine kinome through sequence evolution, and we also provide novel hypotheses of undiscovered kinase functions.