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

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‐c...

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Bibliographic Details
Published in:The EMBO journal 2003-06, Vol.22 (11), p.2571-2582
Main Authors: Feller, Stephan M, Harkiolaki, Maria, Lewitzky, Marc, Gilbert, Robert J.C, Jones, EYvonne, Bourette, Roland P, Mouchiroud, Guy, Sondermann, Holger, Moarefi, Ismail
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Amino Acid Sequence
Animals
Binding Sites
Carrier Proteins
Carrier Proteins - chemistry
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cellular Biology
crystal structure
Crystallography, X-Ray
Dimerization
Electrostatics
Gads
Humans
Hydrogen Bonding
In Vitro Techniques
Life Sciences
Mice
Models, Molecular
Molecular Sequence Data
Mona
Phosphoproteins
Phosphoproteins - chemistry
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phylogeny
Protein Binding
Recombinant Proteins
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Sequence Homology, Amino Acid
SH3 domain dimer
SLP-76
src Homology Domains
Static Electricity
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Summary: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.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/cdg258