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PDBsum entry 1mkc
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Heparin-binding growth factor
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PDB id
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1mkc
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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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Solution structure of midkine, A new heparin-Binding growth factor.
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Authors
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W.Iwasaki,
K.Nagata,
H.Hatanaka,
T.Inui,
T.Kimura,
T.Muramatsu,
K.Yoshida,
M.Tasumi,
F.Inagaki.
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Ref.
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EMBO J, 1997,
16,
6936-6946.
[DOI no: ]
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PubMed id
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Abstract
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Midkine (MK) is a 13 kDa heparin-binding polypeptide which enhances neurite
outgrowth, neuronal cell survival and plasminogen activator activity. MK is
structurally divided into two domains, and most of the biological activities are
located on the C-terminal domain. The solution structures of the two domains
were determined by NMR. Both domains consist of three antiparallel beta-strands,
but the C-terminal domain has a long flexible hairpin loop where a
heparin-binding consensus sequence is located. Basic residues on the beta-sheet
of the C-terminal domain form another heparin-binding site. Measurement of NMR
signals in the presence of a heparin oligosaccharides verified that multiple
amino acids in the two sites participated in heparin binding. The MK dimer has
been shown to be the active form, giving signals to endothelial cells and
probably to neuronal cells. We present a head-to-head dimer model of MK. The
model was supported by the results of cross-linking experiments using
transglutaminase. The dimer has a fused heparin-binding site at the dimer
interface of the C-terminal domain, and the heparin-binding sites on MK fit the
sulfate group clusters on heparin. These features are consistent with the
proposed stronger heparin-binding activity and biological activity of the dimer.
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Figure 5.
Figure 5 Number of inter-residue NOE constraints and r.m.s.d.s
for each residue of (A) MK(1 -59) and (B) MK(62 -104). The
number of sequential distance constraints (gray bars),
medium-range distance constraints with 2  |i
-j|
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Figure 10.
Figure 10 The model for binding of MK(62 -104) dimer on the
heparin 20mer units with two conformations. (A) The model for
heparin and MK(62 -104) head-to-head dimer complex (blue, basic
residues; red, acidic residues; green, Gln; and pink, oxygens of
sulfate groups). Positively charged clusters (blue dotted
circles) of MK(62 -104) fit to negatively charged clusters (pink
dotted circles) of heparin. (B) The opposite surface of MK(62
-104) to that shown in (A). The acidic residues of MK(62 -104)
are localized opposite the heparin-binding surface. Gln95 which
is attacked by transglutaminase is exposed opposite to the
heparin-binding surface and is in close proximity to Lys63 on
the counterpart. Lys63 is thought to be an amine donor in the
transglutaminase reaction. (C) Side view of (A). The sulfate
groups are localized on the right and left sides of the heparin
molecule. Basic charged clusters in MK(62 -104) dimer fit the
clusters of sulfate groups.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(1997,
16,
6936-6946)
copyright 1997.
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