Proline isomerization preorganizes the Itk SH2 domain for binding to the Itk SH3 domain.
We report here the NMR-derived structure of the binary complex formed by the interleukin-2 tyrosine kinase (Itk) Src homology 3 (SH3) and Src homology 2 (SH2) domains. The interaction is independent of both a phosphotyrosine motif and a proline-rich sequence, the classical targets of the SH2 and SH3 domains, respectively. The Itk SH3/SH2 structure reveals the molecular details of this nonclassical interaction and provides a clear picture for how the previously described prolyl cis/trans isomerization present in the Itk SH2 domain mediates SH3 binding. The higher-affinity cis SH2 conformer is preorganized to form a hydrophobic interface with the SH3 domain. The structure also provides insight into how autophosphorylation in the Itk SH3 domain might increase the affinity of the intermolecular SH3/SH2 interaction. Finally, we can compare this Itk complex with other examples of SH3 and SH2 domains engaging their ligands in a nonclassical manner. These small binding domains exhibit a surprising level of diversity in their binding repertoires.
Severin
Andrew
A
Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50010, USA.
Joseph
Raji E
RE
Boyken
Scott
S
Fulton
D Bruce
DB
Andreotti
Amy H
AH
D000818:Animals; D001665:Binding Sites; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
D008024:Ligands; D011392:Proline; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase