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PDBsum entry 1khx
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Transcription
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PDB id
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1khx
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of a phosphorylated smad2. Recognition of phosphoserine by the mh2 domain and insights on smad function in tgf-Beta signaling.
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Authors
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J.W.Wu,
M.Hu,
J.Chai,
J.Seoane,
M.Huse,
C.Li,
D.J.Rigotti,
S.Kyin,
T.W.Muir,
R.Fairman,
J.Massagué,
Y.Shi.
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Ref.
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Mol Cell, 2001,
8,
1277-1289.
[DOI no: ]
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PubMed id
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Abstract
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Ligand-induced phosphorylation of the receptor-regulated Smads (R-Smads) is
essential in the receptor Ser/Thr kinase-mediated TGF-beta signaling. The
crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the
formation of a homotrimer mediated by the C-terminal phosphoserine (pSer)
residues. The pSer binding surface on the MH2 domain, frequently targeted for
inactivation in cancers, is highly conserved among the Co- and R-Smads. This
finding, together with mutagenesis data, pinpoints a functional interface
between Smad2 and Smad4. In addition, the pSer binding surface on the MH2 domain
coincides with the surface on R-Smads that is required for docking interactions
with the serine-phosphorylated receptor kinases. These observations define a
bifunctional role for the MH2 domain as a pSer-X-pSer binding module in receptor
Ser/Thr kinase signaling pathways.
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Figure 4.
Figure 4. A Close-Up View of the Interactions between the
Phosphorylated C Terminus from One Monomer and the Loop-Strand
Pocket of the Adjacent Monomer(A) An electron density map of the
phosphorylated C terminus. The 2F[o]-F[c] map (omit map), shown
in pink, was contoured at 1.5σ and was calculated by simulated
annealing using CNS (Brunger et al., 1998) with the omission of
the C-terminal five residues. The backbone as well as the side
chains of four residues are shown in yellow.(B) An overall view
of the interactions. The C terminus is shown as a yellow coil,
while its binding partner is represented as a transparent
surface with backbones in pink. The side chains of the last five
residues in the C terminus (CSSMS) and the basic residues in the
loop-strand pocket are shown.(C) A stereo view of hydrogen bond
networks. The two interacting monomers are shown in green and
blue, respectively. Their side chains are colored gold and
yellow. Hydrogen bonds among oxygen (red) and nitrogen (blue)
atoms and water molecules (red) are indicated by red dashed
lines.(D) A stereo view of the van der Waals contacts between
the phosphorylated C terminus from one monomer and the
loop-strand pocket of the adjacent monomer. The coloring scheme
is the same as in (C).
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Figure 6.
Figure 6. Implications for RSK-Mediated Signaling(A)
Proposed mechanisms of Smad2 dissociation from the receptor
kinase (TβRI) (Huse et al., 1999) after phosphorylation. The
positively charged loop-strand pocket on Smad2, which is
responsible for binding the phosphorylated C terminus of another
Smad2, coincides with the L3 loop region, which is involved in
interactions with the L45 loop and the GS region of the receptor
kinase. The mutual exclusion is proposed to lead to dissociation
of phosphorylated Smad2 from the receptors.(B) A schematic
diagram of signal flow in the RSK-mediated signaling,
highlighting the MH2 domain as the pSer binding motif.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2001,
8,
1277-1289)
copyright 2001.
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