Multiple features of the p59(fyn) src homology 4 domain define a motif for immune-receptor tyrosine-based activation motif (ITAM) binding and for plasma membrane localization

The src family tyrosine kinase p59(fyn) binds to a signaling motif contained in subunits of the TCR known as the immune-receptor tyrosine-based activation motif (ITAM), This is a specific property of p59(fyn) because two related src family kinases, p60(src) and p56(lck) do not bind to ITAMs. In this study, we identify the residues of p59(fyn) that are required for binding to ITAMs. We previously demonstrated that the first 10 residues of p59(fyn) direct its association with the ITAM, Because this region of src family kinases also directs their fatty acylation and membrane association (Resh, M.D. 1993. Biochim. Biophys. Acta. 1155:307-322; Resh, M.D. 1994, Cell. 76:411-413), we determined whether fatty acylation and membrane association of p59(fyn) correlates with its ability to bind ITAMs, Four residues (Gly2, Cys3, Lys7, and Lys9) were required for efficient binding of p59(fyn) to the TCR. Interestingly, the same four residues are present in p56(lyn), the other src family tyrosine kinase known to bind to the ITAM, suggesting that this set of residues constitutes an ITAM recognition motif, These residues were also required for efficient fatty acylation (myristoylation at Gly2 and palmitoylation at Cys3), and plasma membrane targeting of p59(fyn). Thus, the signals that direct p59(fyn) fatty acylation and plasma membrane targeting also direct its specific ability to bind to TCR proteins.