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PDBsum entry 2v5m
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Cell adhesion
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PDB id
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2v5m
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References listed in PDB file
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Key reference
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Title
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Structural basis of dscam isoform specificity.
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Authors
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R.Meijers,
R.Puettmann-Holgado,
G.Skiniotis,
J.H.Liu,
T.Walz,
J.H.Wang,
D.Schmucker.
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Ref.
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Nature, 2007,
449,
487-491.
[DOI no: ]
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PubMed id
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Abstract
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The Dscam gene gives rise to thousands of diverse cell surface receptors thought
to provide homophilic and heterophilic recognition specificity for neuronal
wiring and immune responses. Mutually exclusive splicing allows for the
generation of sequence variability in three immunoglobulin ecto-domains, D2, D3
and D7. We report X-ray structures of the amino-terminal four immunoglobulin
domains (D1-D4) of two distinct Dscam isoforms. The structures reveal a
horseshoe configuration, with variable residues of D2 and D3 constituting two
independent surface epitopes on either side of the receptor. Both isoforms
engage in homo-dimerization coupling variable domain D2 with D2, and D3 with D3.
These interactions involve symmetric, antiparallel pairing of identical peptide
segments from epitope I that are unique to each isoform. Structure-guided
mutagenesis and swapping of peptide segments confirm that epitope I, but not
epitope II, confers homophilic binding specificity of full-length Dscam
receptors. Phylogenetic analysis shows strong selection of matching peptide
sequences only for epitope I. We propose that peptide complementarity of
variable residues in epitope I of Dscam is essential for homophilic binding
specificity.
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Figure 1.
Figure 1: Structure of the N-terminal four-domain fragment of
Dscam. a, Representative class averages from negatively
stained Dscam D1–D8[1.34.30] show that the molecule can adopt
different conformations but retains the horseshoe configuration
of the N-terminal D1–D4 domains. Scale bar, 10 nm. b,
Representative class averages from negatively stained Dscam
D1–D4[1.34] show that the four domains of Dscam D1–D4[1.34]
are arranged in a horseshoe configuration. Scale bar, 5 nm. c,
Ribbon diagram of Dscam D1–D4[1.34] coloured according to
sequence variability; conserved residues are coloured cyan,
variable residues are green and hypervariable residues are red.
The variability was calculated using Shannon's uncertainty^22,
and residues were classified as hypervariable if the uncertainty
value exceeded two-thirds of the highest value observed for all
residues from exons 4 and 6. d, e, Surface representation of
epitope I (left) and II (right) on either side of the horseshoe
for Dscam D1–D4[1.34] (d) and Dscam D1–D4[9.9] (e). Colour
codes are as in c. The figure was prepared using PyMOL
(http://www.pymol.org).
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Figure 2.
Figure 2: Homophilic dimers observed in the crystal lattice.
a, b, Ribbon diagram of the dimer in Dscam D1–D4[1.34] (a) and
Dscam D1–D4[9.9 ](b). D1 and D4, green; D2 and D3, blue for
monomer A; D1 and D4, yellow; D2 and D3, cyan for monomer B.
Residues at symmetry centre are underlined. The isoform-specific
interaction elements are shown as red and orange in molecules A
and B, respectively, and are displayed in more detail along
their respective twofold axes: c, the D2^A–D2^B interface of
Dscam D1–D4[1.34]; d, the D2^A–D2^B interface of Dscam
D1–D4[9.9] (blue and cyan residues are constant); e, the
D3^A–D3^B interface of Dscam D1–D4[1.34]; f, the D3^A–D3^B
interface of Dscam D1–D4[9.9]. Residues involved in
dimer-sustaining hydrogen bonds are labelled and the dyad axes
are displayed as black ellipsoids. The figure was prepared using
PyMOL (http://www.pymol.org).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2007,
449,
487-491)
copyright 2007.
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