|Title||Multimeric and differential binding of CIN85/CD2AP with two atypical proline-rich sequences from CD2 and Cbl-b*.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Ceregido Pérez, M de los Á., A. Garcia-Pino, J. L. Ortega-Roldan, S. Casares, O. López Mayorga, J. Bravo, N. A. J. van Nuland, and A. I. Azuaga|
|Date Published||2013 Jul|
|Keywords||Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Antigens, CD2, Cytoskeletal Proteins, Humans, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Proline, Protein Binding, Protein Structure, Secondary, Proto-Oncogene Proteins c-cbl, Scattering, Small Angle, src Homology Domains, Thermodynamics, Titrimetry, X-Ray Diffraction|
The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology 3 (SH3) domains to cluster protein partners and ensure efficient signal transduction and down-regulation of tyrosine kinase receptors. Using NMR, isothermal titration calorimetry and small-angle X-ray scattering methods, we have characterized several binding modes of the N-terminal SH3 domain (SH3A) of CD2AP and CIN85 with two natural atypical proline-rich regions in CD2 (cluster of differentiation 2) and Cbl-b (Casitas B-lineage lymphoma), and compared these data with previous studies and published crystal structures. Our experiments show that the CD2AP-SH3A domain forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a type II complex with CD2, but a trimeric complex with Cbl-b, whereby the type I and II interactions take place at the same time. Together, these results explain how multiple interactions among similar SH3 domains and ligands produce a high degree of diversity in tyrosine kinase, cell adhesion or T-cell signaling pathways.
|Alternate Journal||FEBS J.|