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Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76.
Maria Harkiolaki1, Marc Lewitzky, Robert J C Gilbert
1Cancer Research UK Cell Signalling Group and Weatherall Institute of Molecular Medicine, Oxford, UK.
The EMBO Journal
|May 30, 2003
Summary
The SH3 domain of Mona/Gads binds SLP-76 via a novel clamp-like structure, not the typical poly-proline motif. This unique binding interaction and ion-dependent dimerization reveal new insights into SH3 domain regulation.
Area of Science:
- Molecular biology
- Structural biology
- Biochemistry
Background:
- SH3 domains are crucial protein recognition modules involved in cellular signaling.
- Understanding SH3 domain binding selectivity is vital due to over 500 human SH3 domains.
- The Grb2-like adaptor Mona/Gads interacts with the T-cell receptor transducer SLP-76.
Purpose of the Study:
- To elucidate the structural basis of the interaction between the Mona/Gads C-terminal SH3 domain (SH3C) and SLP-76.
- To investigate the binding mechanism and affinity of this specific SH3-peptide complex.
- To explore potential novel regulatory mechanisms for SH3 domain function.
Main Methods:
- X-ray crystallography to determine the 1.7 Å resolution structure of the Mona/Gads SH3C-SLP-76 peptide complex.
- Analysis of non-canonical binding motifs and secondary structures.
- Investigation of ion-dependent dimerization in crystal and solution.
Main Results:
- The SLP-76 peptide adopts an unusual clamp-like conformation, lacking the canonical P-x-x-P motif and poly-proline type II helix.
- A central R-x-x-K motif forms a 3(10) helix, engaging a charged pocket on SH3C, complemented by hydrophobic interactions.
- This creates a high-affinity, short linear binding epitope.
- The SH3C exhibits ion-dependent dimerization in both crystal and solution states.
Conclusions:
- The Mona/Gads SH3C-SLP-76 interaction represents a novel binding mode for SH3 domains.
- The identified binding mechanism provides a molecular basis for high-affinity recognition.
- Ion-dependent dimerization suggests a new regulatory pathway for SH3 domain activity.