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J. Biol. Chem., Vol. 275, Issue 21, 16174-16182, May 26, 2000
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From the Department of Medicinal Chemistry and Molecular
Pharmacology, Purdue University,
West Lafayette, Indiana 47907-1333
The immunoreceptor tyrosine-based activation
motif (ITAM) plays a central role in transmembrane signal transduction
in hematopoietic cells by mediating responses leading to proliferation
and differentiation. An initial signaling event following activation of
the B cell antigen receptor is phosphorylation of the CD79a (Ig-
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*
)
ITAM by Lyn, a Src family protein-tyrosine kinase. To elucidate the
structural basis for recognition between the ITAM substrate and
activated Lyn kinase, the structure of an ITAM-derived peptide bound to Lyn was determined using exchange-transferred nuclear Overhauser NMR
spectroscopy. The bound substrate structure has an irregular helix-like
character. Docking based on the NMR data into the active site of the
closely related Lck kinase strongly favors ITAM binding in an
orientation similar to binding of cyclic AMP-dependent
protein kinase rather than that of insulin receptor tyrosine kinase.
The model of the complex provides a rationale for conserved ITAM
residues, substrate specificity, and suggests that substrate binds only the active conformation of the Src family tyrosine kinase, unlike the
ATP cofactor, which can bind the inactive form.
*
The work was supported by National Institutes of Health
Grants K04GM00661 and R01GM39478 (to C. B. P.), R01CA37372
(to R. L. G.), and R01GM48099 (to M. L. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Medicinal
Chemistry, Purdue University, West Lafayette, IN 47906-1333. Tel.:
765-494-5980; Fax: 765-496-1189; E-mail: cbp@cc.purdue.edu.
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