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PDBsum entry 1h3h

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protein Protein-protein interface(s) links
Protein-binding PDB id
1h3h
Jmol
Contents
Protein chains
60 a.a. *
11 a.a. *
* Residue conservation analysis
PDB id:
1h3h
Name: Protein-binding
Title: Structural basis for specific recognition of an rxxk-containing slp-76 peptide by the gads c-terminal sh3 domain
Structure: Grb2-related adaptor protein 2. Chain: a. Fragment: c-terminal sh3 domain, residues 263-322. Synonym: gads protein, grblg, grb2l. Engineered: yes. Lymphocyte cytosolic protein 2. Chain: b. Fragment: residues 226-235. Synonym: slp-76.
Source: Mus musculus. House mouse. Organism_taxid: 10090. Cell: t-lymphocyte. Expressed in: escherichia coli. Expression_system_taxid: 469008. Homo sapiens. Human. Organism_taxid: 9606.
NMR struc: 20 models
Authors: Q.Liu,D.Berry,P.Nash,T.Pawson,C.J.Mcglade,S.S.Li
Key ref:
Q.Liu et al. (2003). Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition. Mol Cell, 11, 471-481. PubMed id: 12620234 DOI: 10.1016/S1097-2765(03)00046-7
Date:
03-Sep-02     Release date:   06-Mar-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O89100  (GRAP2_MOUSE) -  GRB2-related adaptor protein 2
Seq:
Struc:
322 a.a.
60 a.a.
Protein chain
Pfam   ArchSchema ?
Q13094  (LCP2_HUMAN) -  Lymphocyte cytosolic protein 2
Seq:
Struc:
 
Seq:
Struc:
533 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
DOI no: 10.1016/S1097-2765(03)00046-7 Mol Cell 11:471-481 (2003)
PubMed id: 12620234  
 
 
Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition.
Q.Liu, D.Berry, P.Nash, T.Pawson, C.J.McGlade, S.S.Li.
 
  ABSTRACT  
 
The SH3 domain, which normally recognizes proline-rich sequences, has the potential to bind motifs with an RxxK consensus. To explore this novel specificity, we have determined the solution structure of the Gads T cell adaptor C-terminal SH3 domain in complex with an RSTK-containing peptide, representing its physiological binding site on the SLP-76 docking protein. The SLP-76 peptide engages four distinct binding pockets on the surface of the Gads SH3 domain and upon binding adopts a unique structure characterized by a right-handed 3(10) helix at the RSTK locus, in contrast to the left-handed polyproline type II helix formed by canonical proline-rich SH3 ligands. The structure, and supporting mutagenesis and peptide binding data, reveal a novel mode of ligand recognition by SH3 domains.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Solution Structure of a Gads SH3-C Domain – SLP-76 Peptide Complex(A) Stereo view of a superposition of 20 lowest-energy structures of the Gads SH3-C domain – SLP-76 peptide complex in backbone traces. The Gads SH3-C domain (residues 265–321) is shown in green and the SLP-76 peptide in violet. The peptide has the sequence A^1PSIDRSTKPA^11, of which the first ten residues were taken from the Gads SH3-C – binding site in SLP-76, and the last Ala was added to reduce end effects. Ala11 does not interact with the SH3 domain (see Figure 3B) and is hence omitted from all figures for clarity.(B) Ribbon representation of the same complex generated using coordinates of the lowest-energy structure. The β strands and the RT- and n-Src loops of the SH3 domain are labeled in black. The peptide backbone is depicted in violet with side chains shown in pale green or dark green (for residues located at the peptide-protein interface).
Figure 2.
Figure 2. A Comparison of Peptide Binding Surfaces between the Gads and c-Src SH3 Domains(A) Surface representation of the Gads SH3-C domain – SLP-76 peptide complex. Areas of positive and negative charges are shown in blue and red, respectively. Residues in the peptides that occupy the four binding pockets on the SH3 domain surface (identified in dotted circles) are labeled in black. Residue Glu275 of the protein, which encloses the second pocket, is labeled in red.(B) Surface representation of the c-Src SH3 domain – APP12 peptide complex (adapted from Feng et al., 1995). APP12 is a dodecapeptide that binds with high affinity to the c-Src SH3 domain (Kd = 1.2 μM). Since the last four residues of the peptide do not contribute significantly to SH3 binding (Feng et al., 1995), only the first eight residues of the peptide (A^1PPLPPRN^8) are shown for clarity. As in (A), key residues in peptide APP12 that engage the three binding pockets (identified as dotted circles) on the c-Src SH3 domain are labeled.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 11, 471-481) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21349274 M.Primeau, A.Ben Djoudi Ouadda, and N.Lamarche-Vane (2011).
Cdc42 GTPase-activating protein (CdGAP) interacts with the SH3D domain of Intersectin through a novel basic-rich motif.
  FEBS Lett, 585, 847-853.  
21227701 T.Kaneko, S.S.Sidhu, and S.S.Li (2011).
Evolving specificity from variability for protein interaction domains.
  Trends Biochem Sci, 36, 183-190.  
20005866 C.B.McDonald, K.L.Seldeen, B.J.Deegan, V.Bhat, and A.Farooq (2010).
Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control.
  Arch Biochem Biophys, 494, 216-225.  
20457812 J.A.Grasis, D.M.Guimond, N.R.Cam, K.Herman, P.Magotti, J.D.Lambris, and C.D.Tsoukas (2010).
In vivo significance of ITK-SLP-76 interaction in cytokine production.
  Mol Cell Biol, 30, 3596-3609.  
20707603 M.Barilari, and L.Dente (2010).
The neuronal proteins CIPP, Cypin and IRSp53 form a tripartite complex mediated by PDZ and SH3 domains.
  Biol Chem, 391, 1169-1174.  
19323566 C.B.McDonald, K.L.Seldeen, B.J.Deegan, and A.Farooq (2009).
SH3 domains of Grb2 adaptor bind to PXpsiPXR motifs within the Sos1 nucleotide exchange factor in a discriminate manner.
  Biochemistry, 48, 4074-4085.  
  20107536 G.A.Koretzky (2009).
The Role of SH2 Domain-containing Leukocyte Phosphoprotein of 76 kDa in the Regulation of Immune Cell Development and Function.
  Immune Netw, 9, 75-83.  
19656396 J.Vyas, R.J.Nowling, M.W.Maciejewski, S.Rajasekaran, M.R.Gryk, and M.R.Schiller (2009).
A proposed syntax for Minimotif Semantics, version 1.
  BMC Genomics, 10, 360.  
19168626 P.J.Mintz, M.Cardó-Vila, M.G.Ozawa, A.Hajitou, R.Rangel, L.Guzman-Rojas, D.R.Christianson, M.A.Arap, R.J.Giordano, G.R.Souza, J.Easley, A.Salameh, S.Oliviero, R.R.Brentani, E.Koivunen, W.Arap, and R.Pasqualini (2009).
An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment.
  Proc Natl Acad Sci U S A, 106, 2182-2187.  
19909359 T.Kambayashi, D.F.Larosa, M.A.Silverman, and G.A.Koretzky (2009).
Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation.
  Immunol Rev, 232, 99.  
17993503 O.Moran, M.W.Roessle, R.A.Mariuzza, and N.Dimasi (2008).
Structural features of the full-length adaptor protein GADS in solution determined using small-angle X-ray scattering.
  Biophys J, 94, 1766-1772.  
17010654 N.Dimasi (2007).
Crystal structure of the C-terminal SH3 domain of the adaptor protein GADS in complex with SLP-76 motif peptide reveals a unique SH3-SH3 interaction.
  Int J Biochem Cell Biol, 39, 109-123.
PDB code: 2d0n
16493428 G.A.Koretzky, F.Abtahian, and M.A.Silverman (2006).
SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond.
  Nat Rev Immunol, 6, 67-78.  
16461356 J.S.Duke-Cohan, H.Kang, H.Liu, and C.E.Rudd (2006).
Regulation and function of SKAP-55 non-canonical motif binding to the SH3c domain of adhesion and degranulation-promoting adaptor protein.
  J Biol Chem, 281, 13743-13750.  
16766517 K.Ma, J.G.Forbes, G.Gutierrez-Cruz, and K.Wang (2006).
Titin as a giant scaffold for integrating stress and Src homology domain 3-mediated signaling pathways: the clustering of novel overlap ligand motifs in the elastic PEVK segment.
  J Biol Chem, 281, 27539-27556.  
16847311 R.Chen, S.Latour, X.Shi, and A.Veillette (2006).
Association between SAP and FynT: Inducible SH3 domain-mediated interaction controlled by engagement of the SLAM receptor.
  Mol Cell Biol, 26, 5559-5568.  
16756506 R.P.Bhattacharyya, A.Reményi, B.J.Yeh, and W.A.Lim (2006).
Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.
  Annu Rev Biochem, 75, 655-680.  
16622794 Y.Che, B.R.Brooks, and G.R.Marshall (2006).
Development of small molecules designed to modulate protein-protein interactions.
  J Comput Aided Mol Des, 20, 109-130.  
16262684 J.C.Houtman, M.Barda-Saad, and L.E.Samelson (2005).
Examining multiprotein signaling complexes from all angles.
  FEBS J, 272, 5426-5435.  
16061254 L.Deng, C.A.Velikovsky, C.P.Swaminathan, S.Cho, and R.A.Mariuzza (2005).
Structural basis for recognition of the T cell adaptor protein SLP-76 by the SH3 domain of phospholipase Cgamma1.
  J Mol Biol, 352, 1.
PDB codes: 1ywo 1ywp
15880548 L.J.Ball, R.Kühne, J.Schneider-Mergener, and H.Oschkinat (2005).
Recognition of Proline-Rich Motifs by Protein-Protein-Interaction Domains.
  Angew Chem Int Ed Engl, 44, 2852-2869.  
15196557 A.Veillette (2004).
Specialised adaptors in immune cells.
  Curr Opin Cell Biol, 16, 146-155.  
15483625 C.Kojima, A.Hashimoto, I.Yabuta, M.Hirose, S.Hashimoto, Y.Kanaho, H.Sumimoto, T.Ikegami, and H.Sabe (2004).
Regulation of Bin1 SH3 domain binding by phosphoinositides.
  EMBO J, 23, 4413-4422.  
15541653 J.N.Wu, and G.A.Koretzky (2004).
The SLP-76 family of adapter proteins.
  Semin Immunol, 16, 379-393.  
15090612 K.Kowanetz, K.Husnjak, D.Höller, M.Kowanetz, P.Soubeyran, D.Hirsch, M.H.Schmidt, K.Pavelic, P.De Camilli, P.A.Randazzo, and I.Dikic (2004).
CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors.
  Mol Biol Cell, 15, 3155-3166.  
15280876 M.A.Lemmon, and S.J.Smerdon (2004).
Signaling by the sea.
  Nat Struct Mol Biol, 11, 682-685.  
15100220 M.Lewitzky, M.Harkiolaki, M.C.Domart, E.Y.Jones, and S.M.Feller (2004).
Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix.
  J Biol Chem, 279, 28724-28732.
PDB code: 1uti
12829691 A.V.Kurakin, S.Wu, and D.E.Bredesen (2003).
Atypical recognition consensus of CIN85/SETA/Ruk SH3 domains revealed by target-assisted iterative screening.
  J Biol Chem, 278, 34102-34109.  
13129930 T.Kaneko, T.Kumasaka, T.Ganbe, T.Sato, K.Miyazawa, N.Kitamura, and N.Tanaka (2003).
Structural insight into modest binding of a non-PXXP ligand to the signal transducing adaptor molecule-2 Src homology 3 domain.
  J Biol Chem, 278, 48162-48168.
PDB code: 1uj0
12702867 T.Pawson, and P.Nash (2003).
Assembly of cell regulatory systems through protein interaction domains.
  Science, 300, 445-452.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.