Premium
Phosphoinositide, Phosphopeptide and Pyridone Interactions of the Abl SH2 Domain
Author(s) -
Tokonzaba Etienne,
Capelluto Daniel G. S.,
Kutateladze Tatiana G.,
Overduin Michael
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00361.x
Subject(s) - proto oncogene tyrosine protein kinase src , sh2 domain , phosphoserine , peptidomimetic , phosphopeptide , chemistry , sh3 domain , myristoylation , abl , biochemistry , binding site , phosphotyrosine binding domain , microbiology and biotechnology , biology , phosphorylation , signal transduction , peptide , tyrosine kinase , serine
Signaling proteins are localized and regulated by Src homology 2 domains which recognize phosphotyrosine‐containing sequences. Recently, noncanonical ligands have been proposed for Src homology 2 domains including that of Abl and its breakpoint cluster region fusion, which causes chronic myelogenous leukemia. Here, the Abl Src homology 2 domain's binding sites and affinities for phosphotyrosine‐ and phosphoserine‐containing motifs, phosphoinositides as well as a pyridone‐based peptidomimetic inhibitor were determined using nuclear magnetic resonance spectroscopy in order to define their roles. The cognate Crk peptide ligand was bound with an affinity of 69 μ M and, like the higher affinity peptidomimetic, engages the phosphotyrosine and +3 hydrophobic pockets while putative phosphoserine‐containing breakpoint cluster region ligands are ruled out. Surprisingly, phosphatidylinositol 4, 5 bisphosphate interacts with an overlapping site through an electrostatic mechanism that does not appear to involve hydrophobic insertion into micelles. The conserved Arg36 residue in the FLVRES motif is required for both phosphotyrosine binding and for localization to phosphatidylinositol 4, 5 bisphosphate–containing liposomes, while Arg59 in the β D strand is necessary for the phosphoinositide interaction. Thus the Src homology 2 domain of Abl, a myristoylated and membrane‐localized protein, is able to interact directly with phosphoinositides through a multifunctional basic site that overlaps the phosphotyrosine pocket.