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

EMBO J. 2003 Jun 2;22(11):2571-82. doi: 10.1093/emboj/cdg258.


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 A. 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 beta-barrel. The central R-x-x-K motif of the peptide forms a 3(10) 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Hydrogen Bonding
  • In Vitro Techniques
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphoproteins / chemistry*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phylogeny
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Static Electricity
  • src Homology Domains


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GRAP2 protein, human
  • Mona protein, mouse
  • Phosphoproteins
  • Recombinant Proteins
  • SLP-76 signal Transducing adaptor proteins

Associated data