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NMR structure of phospho‐tyrosine signaling complexes
Author(s) -
Post Carol Beth,
Gaul Beverly S.,
Eisenmesser Elan Zohar,
Schneider Michael L.
Publication year - 1999
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/(sici)1098-1128(199907)19:4<295::aid-med3>3.0.co;2-5
Subject(s) - lyn , proto oncogene tyrosine protein kinase src , tyrosine phosphorylation , tyrosine , tyrosine kinase , receptor tyrosine kinase , sh2 domain , biochemistry , tyrosine protein kinase csk , phosphorylation , protein tyrosine phosphatase , chemistry , sh3 domain , biology , signal transduction
A structural basis for activation and substrate specificity of src tyrosine kinases, and regulation of protein–protein association by tyrosine phosphorylation is described. Lyn, a src‐family tyrosine kinase, recognizes and phosphorylates the immunoreceptor tyrosine‐based activation motif, ITAM, a critical component in transmembrane signal transduction in hemopoietic cells. The structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine kinase was determined by high‐resolution NMR, and a model of the complex was generated using the crystallographic structure of Lck, a closely related Src‐family kinase. The results provide a rationale for the conserved ITAM residues and specificity of Lyn, and suggest that substrate plays a role in stabilizing the kinase conformation optimal for catalysis. It is our hope that the Lck‐ITAM peptide model complex will be useful in aiding structure‐based drug design efforts that target substrate binding determinants in the design. Concerning the regulation of protein–protein association, we report on a complex between erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde‐3‐phosphate dehydrogenase. The formation of this complex is negatively regulated by tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells, this association results in a decrease in glycolysis due to competitive inhibition of the glycolytic enzymes. The structure of band 3 recognized by the glycolytic enzymes was determined by solution NMR, and found to be a loop structure with tyrosine centrally positioned and excluded from intermolecular contact. This p hosphorylation s ensitive i nteraction, or PSI, loop may be the basis of a general mechanism for negative regulation through tyrosine phosphorylation. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 4, 295–305, 1999.