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* Residue conservation analysis
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PDB id:
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Protein binding
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Title:
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Mona/gads sh3c domain
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Structure:
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Grb2-related adaptor protein 2. Chain: a, b. Fragment: sh3c domain, residues 265-322. Synonym: gads protein, growth factor receptor protein, grblg, grf40 adaptor protein, grf-40, grb-2-like protein, grb2l, grbx, p38, hematopoietic cell-associated adaptor protein grpl, adapter protein grid, sh3-sh2-sh3 adaptor mona. Engineered: yes. Other_details: thrombin cleavage overhang between a-4 and a-1.
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 10090
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Biol. unit:
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Dimer (from PDB file)
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Resolution:
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1.76Å
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R-factor:
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0.174
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R-free:
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0.235
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Authors:
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M.Harkiolaki,M.Lewitzky,R.J.C.Gilbert,E.Y.Jones,R.P.Bourette, G.Mouchiroud,H.Sondermann,I.Moarefi,S.M.Feller
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Key ref:
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M.Harkiolaki
et al.
(2003).
Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76.
EMBO J,
22,
2571-2582.
PubMed id:
DOI:
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Date:
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24-Mar-03
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Release date:
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02-Apr-03
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PROCHECK
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Headers
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References
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O89100
(GRAP2_MOUSE) -
GRB2-related adaptor protein 2 from Mus musculus
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Seq:
Struc:
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322 a.a.
59 a.a.*
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Enzyme class:
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Chains A, B, C, D:
E.C.?
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DOI no:
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EMBO J
22:2571-2582
(2003)
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PubMed id:
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Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76.
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M.Harkiolaki,
M.Lewitzky,
R.J.Gilbert,
E.Y.Jones,
R.P.Bourette,
G.Mouchiroud,
H.Sondermann,
I.Moarefi,
S.M.Feller.
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ABSTRACT
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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.
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Selected figure(s)
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Figure 3.
Figure 3 Two views of the Mona/Gads SH3C structure in complex
with the 13 amino acid SLP-76 peptide (P2).  -strands
are coloured blue and 3[10] helices are shown in orange. (A)
View looking down the length of the -barrel.
(B) View rotated by 90° on the vertical axis.
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Figure 8.
Figure 8 Ribbon representations of the Grb2 SH3C and Mona/Gads
SH3C domains with areas involved in molecular docking of an
SLP-76 peptide coloured blue. (A) Grb2 SH3C–peptide
interactions as previously defined by NMR experiments (Kami et
al., 2002). (B) Mona/Gads SH3C–peptide contacts present in the
crystal structure.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2003,
22,
2571-2582)
copyright 2003.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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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.
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Arch Biochem Biophys,
494,
216-225.
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E.Marcora,
and
M.B.Kennedy
(2010).
The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus.
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Hum Mol Genet,
19,
4373-4384.
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M.Barilari,
and
L.Dente
(2010).
The neuronal proteins CIPP, Cypin and IRSp53 form a tripartite complex mediated by PDZ and SH3 domains.
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Biol Chem,
391,
1169-1174.
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M.Pietrek,
M.M.Brinkmann,
I.Glowacka,
A.Enlund,
A.Hävemeier,
O.Dittrich-Breiholz,
M.Kracht,
M.Lewitzky,
K.Saksela,
S.M.Feller,
and
T.F.Schulz
(2010).
Role of the Kaposi's sarcoma-associated herpesvirus K15 SH3 binding site in inflammatory signaling and B-cell activation.
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J Virol,
84,
8231-8240.
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O.Aitio,
M.Hellman,
A.Kazlauskas,
D.F.Vingadassalom,
J.M.Leong,
K.Saksela,
and
P.Permi
(2010).
Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assembly.
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Proc Natl Acad Sci U S A,
107,
21743-21748.
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PDB code:
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A.Severin,
R.E.Joseph,
S.Boyken,
D.B.Fulton,
and
A.H.Andreotti
(2009).
Proline isomerization preorganizes the Itk SH2 domain for binding to the Itk SH3 domain.
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J Mol Biol,
387,
726-743.
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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.
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Biochemistry,
48,
4074-4085.
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M.Harkiolaki,
T.Tsirka,
M.Lewitzky,
P.C.Simister,
D.Joshi,
L.E.Bird,
E.Y.Jones,
N.O'Reilly,
and
S.M.Feller
(2009).
Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.
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Structure,
17,
809-822.
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PDB codes:
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A.Giubellino,
T.R.Burke,
and
D.P.Bottaro
(2008).
Grb2 signaling in cell motility and cancer.
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Expert Opin Ther Targets,
12,
1021-1033.
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J.J.Rice,
and
P.S.Daugherty
(2008).
Directed evolution of a biterminal bacterial display scaffold enhances the display of diverse peptides.
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Protein Eng Des Sel,
21,
435-442.
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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.
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Biophys J,
94,
1766-1772.
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R.A.Robinson,
X.Lu,
E.Y.Jones,
and
C.Siebold
(2008).
Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73.
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Structure,
16,
259-268.
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PDB code:
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B.T.Seet,
D.M.Berry,
J.S.Maltzman,
J.Shabason,
M.Raina,
G.A.Koretzky,
C.J.McGlade,
and
T.Pawson
(2007).
Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif.
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EMBO J,
26,
678-689.
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J.Brown,
C.A.O'Callaghan,
A.S.Marshall,
R.J.Gilbert,
C.Siebold,
S.Gordon,
G.D.Brown,
and
E.Y.Jones
(2007).
Structure of the fungal beta-glucan-binding immune receptor dectin-1: implications for function.
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Protein Sci,
16,
1042-1052.
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PDB codes:
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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.
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Int J Biochem Cell Biol,
39,
109-123.
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PDB code:
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S.Niendorf,
A.Oksche,
A.Kisser,
J.Löhler,
M.Prinz,
H.Schorle,
S.Feller,
M.Lewitzky,
I.Horak,
and
K.P.Knobeloch
(2007).
Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo.
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Mol Cell Biol,
27,
5029-5039.
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A.Geerlof,
J.Brown,
B.Coutard,
M.P.Egloff,
F.J.Enguita,
M.J.Fogg,
R.J.Gilbert,
M.R.Groves,
A.Haouz,
J.E.Nettleship,
P.Nordlund,
R.J.Owens,
M.Ruff,
S.Sainsbury,
D.I.Svergun,
and
M.Wilmanns
(2006).
The impact of protein characterization in structural proteomics.
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Acta Crystallogr D Biol Crystallogr,
62,
1125-1136.
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C.Gu,
S.G.Tangye,
X.Sun,
Y.Luo,
Z.Lin,
and
J.Wu
(2006).
The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation.
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Proc Natl Acad Sci U S A,
103,
14447-14452.
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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.
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J Biol Chem,
281,
13743-13750.
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M.R.Schiller,
K.Chakrabarti,
G.F.King,
N.I.Schiller,
B.A.Eipper,
and
M.W.Maciejewski
(2006).
Regulation of RhoGEF activity by intramolecular and intermolecular SH3 domain interactions.
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J Biol Chem,
281,
18774-18786.
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PDB code:
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M.Slevin,
A.B.Elasbali,
M.Miguel Turu,
J.Krupinski,
L.Badimon,
and
J.Gaffney
(2006).
Identification of differential protein expression associated with development of unstable human carotid plaques.
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Am J Pathol,
168,
1004-1021.
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N.J.Hassan,
S.J.Simmonds,
N.G.Clarkson,
S.Hanrahan,
M.J.Puklavec,
M.Bomb,
A.N.Barclay,
and
M.H.Brown
(2006).
CD6 regulates T-cell responses through activation-dependent recruitment of the positive regulator SLP-76.
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Mol Cell Biol,
26,
6727-6738.
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O.Kristensen,
S.Guenat,
I.Dar,
N.Allaman-Pillet,
A.Abderrahmani,
M.Ferdaoussi,
R.Roduit,
F.Maurer,
J.S.Beckmann,
J.S.Kastrup,
M.Gajhede,
and
C.Bonny
(2006).
A unique set of SH3-SH3 interactions controls IB1 homodimerization.
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EMBO J,
25,
785-797.
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PDB codes:
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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.
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Annu Rev Biochem,
75,
655-680.
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X.You,
A.W.Nguyen,
A.Jabaiah,
M.A.Sheff,
K.S.Thorn,
and
P.S.Daugherty
(2006).
Intracellular protein interaction mapping with FRET hybrids.
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Proc Natl Acad Sci U S A,
103,
18458-18463.
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C.Reichman,
K.Singh,
Y.Liu,
S.Singh,
H.Li,
J.E.Fajardo,
A.Fiser,
and
R.B.Birge
(2005).
Transactivation of Abl by the Crk II adapter protein requires a PNAY sequence in the Crk C-terminal SH3 domain.
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Oncogene,
24,
8187-8199.
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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.
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J Mol Biol,
352,
1.
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PDB codes:
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A.Veillette
(2004).
Specialised adaptors in immune cells.
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Curr Opin Cell Biol,
16,
146-155.
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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.
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J Biol Chem,
279,
28724-28732.
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PDB code:
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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.
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Links
