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Speaker: Carol B. Post, Distinguished Professor Medicinal Chemistry & Mol. Pharmacol., Purdue University, West Lafayette, IN
Title:Discovering Functional Mechanisms of Syk and Src Tyrosine Kinases
Abstract: Most signal transduction pathways in humans are regulated by protein kinases through phosphorylation of their protein substrates. Typical eukaryotic protein kinases are of two major types: those that phosphorylate specific sequences containing tyrosine (~90 kinases) and those that phosphorylate either serine or threonine (~395 kinases). This talk will focus on two non-receptor tyrosine kinases: Syk and Src, both of which have been targeted by drug development efforts related to autoimmune disease and cancer. Syk is largely known as a master regulator in the adaptive immune response by signaling through membrane immune receptors, but more recent studies find Syk is required for cytosolic processes related to autophagy. Syk has two SH2 domains connected by an interdomain linker that mediate Syk binding to immune receptors through a high-affinity association requiring both SH2 domains. We have discovered a novel mechanism of post- translational modification by phosphorylation that regulates Syk-receptor association by an entropy-driven process. The NMR and computer simulation studies leading to this mechanism will be described in this talk.
A second story to be presented relates to substrate recognition by Src kinase. Data from NMR paramagnetic relaxation and modeling with restrained molecular dynamics simulations support the premise that Src substrate recognition differs from other tyrosine kinases. That is, we propose that Src binds the substrate polypeptide chain C-terminal to the phosphoacceptor residue in an orientation that is unlike other tyrosine kinases and more similar to serine/threonine kinases. Selectivity is an underlying concern in developing drugs against kinases. It is therefore a hope that drug development efforts will be aided by understanding specific mechanistic details of kinase protein interactions, such as the ones described in this talk.