期刊
FEBS JOURNAL
卷 280, 期 14, 页码 3399-3415出版社
WILEY-BLACKWELL
DOI: 10.1111/febs.12333
关键词
CIN85; CD2AP; ITC; NMR; SAXS; SH3 domain
资金
- Junta de Andalucia [FQM02838]
- Formacion de Profesorado Universitario (FPU) from the Ministerio de Educacion de Espana
- Vlaams Instituut voor Biotechnologie and the Flanders Hercules Foundation
- Ministerio de Ciencia e Innovacion [SAF2009-10667, SAF2012-31405]
- Generalitat Valenciana [ACOMP/2012/024]
The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology3 (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 differentiation2) 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 typeII dimer with CD2 and both typeI and typeII dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a typeII 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.
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