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Structural characterization of Lyn‐SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinity
Author(s) -
Bauer Finn,
Schweimer Kristian,
Meiselbach Heike,
Hoffmann Silke,
Rösch Paul,
Sticht Heinrich
Publication year - 2005
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.051563605
Subject(s) - lyn , sh3 domain , proto oncogene tyrosine protein kinase src , src family kinase , kinase , binding site , tyrosine kinase , plasma protein binding , chemistry , biology , crystallography , biophysics , biochemistry , signal transduction
The Src homology 3 (SH3) domain of the Src family kinase Lyn binds to the herpesviral tyrosine kinase interacting protein (Tip) more than one order of magnitude stronger than other closely related members of the Src family. In order to identify the molecular basis for high‐affinity binding, the structure of free and Tip‐bound Lyn‐SH3 was determined by NMR spectroscopy. Tip forms additional contacts outside its classical proline‐rich recognition motif and, in particular, a strictly conserved leucine (L186) of the C‐terminally adjacent sequence stretch packs into a hydrophobic pocket on the Lyn surface. Although the existence of this pocket is no unique property of Lyn‐SH3, Lyn is the only Src family kinase that contains an additional aromatic residue (H41) in the n‐Src loop as part of this pocket. H41 covers L186 of Tip by forming tight hydrophobic contacts, and model calculations suggest that the increase in binding affinity compared with other SH3 domains can mainly be attributed to these additional interactions. These findings indicate that this pocket can mediate specificity even between otherwise closely related SH3 domains.