|
 |
|
|
| Subject Categories: Signal Transduction |
|
| The EMBO Journal
(2007) 26, 678–689, doi:10.1038/sj.emboj.7601535 Published online 18 January 2007 |
|
| Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif |
|
|
| Bruce T Seet1, 2, Donna M Berry3, Jonathan S Maltzman4, 5, Jacob Shabason4, Monica Raina1, Gary A Koretzky4, 5, 6, C Jane McGlade3 and Tony Pawson1, 2 |
|
|
1 Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 2 Department of Molecular and Medical Genetics. University of Toronto, Toronto, Ontario, Canada 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 4 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA 5 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA 6 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA To whom correspondence should be addressed Tony Pawson, Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Room 1084, Toronto, Ontario, Canada M5G 1X5. Tel: +1 416 586 4800 ext 8262; Fax: +1 416 586 8869; E-mail: pawson@mshri.on.ca Received 2 August 2006; Accepted 4 December 2006; Published online 18 January 2007. |
|
|
|
| Abstract |
|
| The relationship between the binding affinity and specificity of modular interaction domains is potentially important in determining biological signaling responses. In signaling from the T-cell receptor (TCR), the Gads C-terminal SH3 domain binds a core RxxK sequence motif in the SLP-76 scaffold. We show that residues surrounding this motif are largely optimized for binding the Gads C-SH3 domain resulting in a high-affinity interaction (KD=8–20 nM) that is essential for efficient TCR signaling in Jurkat T cells, since Gads-mediated signaling declines with decreasing affinity. Furthermore, the SLP-76 RxxK motif has evolved a very high specificity for the Gads C-SH3 domain. However, TCR signaling in Jurkat cells is tolerant of potential SLP-76 crossreactivity, provided that very high-affinity binding to the Gads C-SH3 domain is maintained. These data provide a quantitative argument that the affinity of the Gads C-SH3 domain for SLP-76 is physiologically important and suggest that the integrity of TCR signaling in vivo is sustained both by strong selection of SLP-76 for the Gads C-SH3 domain and by a capacity to buffer intrinsic crossreactivity. |
|
| Keywords: adaptor protein, protein–protein interaction, quantitative biology, SH3 domain, T-cell signaling |
|
|
|
Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHA multiparametric assessment of oxygen efflux from the brain Journal of Cerebral Blood Flow & Metabolism Original Article The EMBO Journal Article Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76 The EMBO Journal Article (01 Jun 2003) |
|
|
| |
| |
| |
 | Email link to a friend |
| |
 | Download PDF |
| |
 | Full text |
| |
| |
| |
 | Next article |
| |
 | Previous article |
| |
 | Table of contents |
| |
| |
 | Rights and permissions |
| |
 | Reprints |
| |
| |
| |
 Register for table of contents by email | |
| |
| |
| |