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J Biol Chem, Vol. 273, Issue 25, 15325-15328, June 19, 1998
From the Department of Physiology and Biophysics, School of
Medicine, State University of New York at Stony Brook,
Stony Brook, New York 11794-8661
Src family protein-tyrosine kinases possess
several modular domains important for regulation of catalytic activity
and interaction with potential substrates. Here, we explore
interactions between the SH2 domain of Hck, a Src family kinase, and
substrates containing SH2 domain-binding sites. We have synthesized a
series of peptide substrates containing a high affinity SH2 domain
binding site, (phospho)Tyr-Glu-Glu-Ile. We show that the presence of
this sequence in a peptide results in a dramatic increase in the
phosphorylation rate of a second tyrosine located at the N terminus.
Enhanced phosphorylation is not a consequence of stimulation of
enzymatic activity by C-terminal tail displacement but is imparted
instead by a 10-fold reduction in the Km of the
phosphotyrosine-containing peptide when compared with a control. The
isolated catalytic domain of the non-receptor tyrosine kinase Abl does
not show a preference for the pYEEI motif-containing peptide; however,
the preference is restored when the SH2 domain of Src is introduced
into Abl. Furthermore, enhanced phosphorylation is dependent on the
distance between SH2 domain-binding site and phosphorylatable tyrosine, with the minimum distance requirement being seven amino acids. Reversing the orientation of the pYEEI motif with respect to the substrate sequence decreases phosphorylation by down-regulated Hck, but
both orientations are utilized equally well by activated Hck. We
discuss the possible implications of these results for processive
phosphorylation of substrates in vivo by Src family kinases.
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