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PDBsum entry 2h2c
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Cell adhesion
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PDB id
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2h2c
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References listed in PDB file
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Key reference
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Title
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Comparative structural analysis of the erbin pdz domain and the first pdz domain of zo-1. Insights into determinants of pdz domain specificity.
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Authors
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B.A.Appleton,
Y.Zhang,
P.Wu,
J.P.Yin,
W.Hunziker,
N.J.Skelton,
S.S.Sidhu,
C.Wiesmann.
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Ref.
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J Biol Chem, 2006,
281,
22312-22320.
[DOI no: ]
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PubMed id
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Abstract
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We report a structural comparison of the first PDZ domain of ZO-1 (ZO1-PDZ1) and
the PDZ domain of Erbin (Erbin-PDZ). Although the binding profile of Erbin-PDZ
is extremely specific ([D/E][T/S]WV(COOH)), that of ZO1-PDZ1 is similar
([R/K/S/T][T/S][W/Y][V/I/L](COOH)) but broadened by increased promiscuity for
three of the last four ligand residues. Consequently, the biological function of
ZO-1 is also broadened, as it interacts with both tight and adherens junction
proteins, whereas Erbin is restricted to adherens junctions. Structural analyses
reveal that the differences in specificity can be accounted for by two key
differences in primary sequence. A reduction in the size of the hydrophobic
residue at the base of the site(0) pocket enables ZO1-PDZ1 to accommodate larger
C-terminal residues. A single additional difference alters the specificity of
both site(-1) and site(-3). In ZO1-PDZ1, an Asp residue makes favorable
interactions with both Tyr(-1) and Lys/Arg(-3). In contrast, Erbin-PDZ contains
an Arg at the equivalent position, and this side chain cannot accommodate either
Tyr(-1) or Lys/Arg(-3) but, instead, interacts favorably with Glu/Asp(-3). We
propose a model for ligand recognition that accounts for interactions extending
across the entire binding site but that highlights several key specificity
switches within the PDZ domain fold.
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Figure 2.
FIGURE 2. Overall structure of ZO1-PDZ1. A,
crystallographic dimer of ZO1-PDZ1-YL with the PDZ domains
colored red and magenta and the heptapeptide ligands colored
green. Regions in gray represent the tri-glycine linker between
the PDZ domain and the ligand and a tetrapeptide that was fused
to the N terminus as a result of the cloning procedures. B,
stereoscopic representation of ZO1-PDZ1-YL with secondary
structure elements labeled (PDZ domain, gray; heptapeptide,
green). Structural figures were produced with PyMOL (DeLano
Scientific, San Carlos, CA).
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Figure 5.
FIGURE 5. Determinants of PDZ domain specificity. The
structure of ZO1-PDZ1-YL is shown schematically and colored to
highlight the functional elements involved in ligand
recognition. The peptide ligand is colored green (core motif)
and yellow (auxiliary motif). The PDZ domain functional elements
are colored magenta (primary), red (secondary), and blue
(tertiary). The spheres indicate key side chains of the PDZ
domain that contribute to recognition of side chains within the
core ligand motif.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
22312-22320)
copyright 2006.
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Secondary reference #1
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Title
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Convergent and divergent ligand specificity among pdz domains of the lap and zonula occludens (zo) families.
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Authors
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Y.Zhang,
S.Yeh,
B.A.Appleton,
H.A.Held,
P.J.Kausalya,
D.C.Phua,
W.L.Wong,
L.A.Lasky,
C.Wiesmann,
W.Hunziker,
S.S.Sidhu.
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Ref.
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J Biol Chem, 2006,
281,
22299-22311.
[DOI no: ]
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PubMed id
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Figure 2.
FIGURE 2. Peptide ligands for the LAP and ZO-1 PDZ domains.
Sequences are shown for peptides selected from a completely
random phage-displayed library screened against Erbin-PDZ (A),
Densin-PDZ (B), Scrib-PDZ1 (C), Scrib-PDZ2 (D), Scrib-PDZ3 (E),
ZO1-PDZ1 (F), and ZO1-PDZ3 (G). Gray shading indicates sequences
that match the optimal binding motifs defined in the legend for
Fig. 4.
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Figure 4.
FIGURE 4. Binding specificity profiles for the PDZ domains
of the LAP proteins and ZO-1. For each domain, the specificity
at each site is shown, as deduced from the phage data and
affinity assays.  = aromatic/aliphatic
(Phe, Tyr, Trp, Leu, Ile, Val, Lys, Arg). Lys and Arg were
included with the aromatic/aliphatic amino acids because of the
aliphatic portions of their side chains.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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