Substrate recognition by the Lyn protein-tyrosine kinase - NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor

The immunoreceptor tyrosine-based activation motif (ITAM) plays a central r ole in transmembrane signal transduction in hematopoietic cells by mediatin g responses leading to proliferation and differentiation. An initial signal ing event following activation of the B cell antigen receptor is phosphoryl ation of the CD79a (Ig-alpha) ITAM by Lyn, a Src family protein-tyrosine ki nase. To elucidate the structural basis for recognition between the ITAM su bstrate and activated Lyn kinase, the structure of an ITAM-derived peptide bound to Lyn was determined using exchange-transferred nuclear Overhauser N MR spectroscopy. The bound substrate structure has an irregular helix-like character. Docking based on the NMR data into the active site of the closel y related Lck kinase strongly favors ITAM binding in an orientation similar 60 binding of cyclic AMP-dependent protein kinase rather than that of insu lin receptor tyrosine kinase, The model of the complex provides a rationale for conserved ITAM residues, substrate specificity, and suggests that subs trate binds only the active conformation of the Src family tyrosine kinase, unlike the ATP cofactor, which can bind the inactive form.