Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76

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Abstract
SH3 domains are protein recognition modules within many adaptors and enzymes. With more than 500 SH3 domains in the human genome, binding selectivity is a key issue in understanding the molecular basis of SH3 domain interactions. The Grb2‐like adaptor protein Mona/Gads associates stably with the T‐cell receptor signal transducer SLP‐76. The crystal structure of a complex between the C‐terminal SH3 domain (SH3C) of Mona/Gads and a SLP‐76 peptide has now been solved to 1.7 Å. The peptide lacks the canonical SH3 domain binding motif P–x–x–P and does not form a frequently observed poly‐proline type II helix. Instead, it adopts a clamp‐like shape around the circumfence of the SH3C β‐barrel. The central R–x–x–K motif of the peptide forms a 310 helix and inserts into a negatively charged double pocket on the SH3C while several other residues complement binding through hydrophobic interactions, creating a short linear SH3C binding epitope of uniquely high affinity. Interestingly, the SH3C displays ion‐dependent dimerization in the crystal and in solution, suggesting a novel mechanism for the regulation of SH3 domain functions.