The molecular mechanisms by which tyrosine phosphorylation regulates protein function in cellular signal transduction will be investigated by structural and computational studies. This proposal focuses on phosphotyrosyl proteins that are critical to signaling mediated through the B cell receptor (BCR). Phosphorylation of the ITAM region of the BCR by Lyn tyrosine kinase is a first step in intracellular signaling. The interaction between Lyn and a peptide substrate derived from this natural ITAM substrate will be probed by heteronuclear NMR to distinguish between two putative orientations of substrate binding. Lyn kinase activity is regulated by a conformational activation of the kinase associated with tyrosine phosphorylation and interdomain contacts. The nature of these conformational states, and their relationship to catalytic activation will be examined by computational methods based on molecular dynamics. A second protein tyrosine kinase critical to B cell signaling is Syk. Syk is a prime candidate for mediating pathway selection in B cells. The association of Syk with other signaling proteins through SH2 domain interactions will be investigated by NMR to obtain a molecular understanding of how alternative tyrosyl phosphorylated forms of Syk preferentially select different pathways.
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