title: Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76.
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 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.
authors.affiliation: Cancer Research UK Cell Signalling Group and Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Harkiolaki
authors.forename: Marc
authors.initials: M
authors.lastname: Lewitzky
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Roland P
authors.initials: RP
authors.lastname: Bourette
authors.forename: Guy
authors.initials: G
authors.lastname: Mouchiroud
authors.forename: Holger
authors.initials: H
authors.lastname: Sondermann
authors.forename: Ismail
authors.initials: I
authors.lastname: Moarefi
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C409587:GRAP2 protein, human; C498726:Mona protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; C092947:SLP-76 signal Transducing adaptor proteins