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DOI no:
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J Biol Chem
276:4322-4329
(2001)
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PubMed id:
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Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition.
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A.N.Plotnikov,
A.V.Eliseenkova,
O.A.Ibrahimi,
Z.Shriver,
R.Sasisekharan,
M.A.Lemmon,
M.Mohammadi.
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ABSTRACT
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Fibroblast growth factors (FGFs) constitute a large family of heparin-binding
growth factors with diverse biological activities. FGF9 was originally described
as glia-activating factor and is expressed in the nervous system as a potent
mitogen for glia cells. Unlike most FGFs, FGF9 forms dimers in solution with a
K(d) of 680 nm. To elucidate the molecular mechanism of FGF9 dimerization, the
crystal structure of FGF9 was determined at 2.2 A resolution. FGF9 adopts a
beta-trefoil fold similar to other FGFs. However, unlike other FGFs, the N- and
C-terminal regions outside the beta-trefoil core in FGF9 are ordered and
involved in the formation of a 2-fold crystallographic dimer. A significant
surface area (>2000 A(2)) is buried in the dimer interface that occludes a major
receptor binding site of FGF9. Thus, we propose an autoinhibitory mechanism for
FGF9 that is dependent on sequences outside of the beta-trefoil core. Moreover,
a model is presented providing a molecular basis for the preferential affinity
of FGF9 toward FGFR3.
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Selected figure(s)
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Figure 5.
Fig. 5. Structure-based sequence alignment of FGFs.
Sequence alignment was performed using the CLUSTALW (41). All of
the FGFs used in this alignment are human. The location and the
length of the  strands and
 helices
are shown on the top of the sequence alignment. A period
indicates sequence identity to FGF9. A dash represents a gap
introduced to optimize the alignment. FGF9 residues that
participate in dimerization are colored red. In blue are FGF9
residues that constitute the conventional low and high affinity
heparin binding sites. FGF9 residues that localize to the
periphery of the high affinity heparin-binding site and are
predicted to form the distal and central heparin binding sites
are colored green and yellow, respectively.
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Figure 6.
Fig. 6. Mapping of receptor binding sites in FGF9. A, a
model for the FGF9-FGFR1 structure was generated by
superimposition of the C traces
within the -trefoil of
the FGF9 structure onto the corresponding C traces of
FGF2 in the FGF2-FGFR1 structure. Orange, FGF9; green, D2; cyan,
D3; gray, linker region; red, FGF9 regions that are in major
clashes with FGFR1. B, stereo view of the receptor binding sites
on FGF9. FGF9 residues are colored with respect to the FGFR
regions with which they interact. FGF9 residues that interact
with D2 are colored green, residues that interact with the
linker region are colored gray, and residues that interact with
D3 are colored cyan. FGF9 residues that interact with the C'- E loop in D3
of FGFR are colored purple. Color coding for atoms is the same
as Fig. 4. This figure was created using Molscript and Raster3D.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2001,
276,
4322-4329)
copyright 2001.
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Figures were
selected
by an automated process.
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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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D.Spicer
(2009).
FGF9 on the move.
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Nat Genet, 41,
272-273.
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M.Harada,
H.Murakami,
A.Okawa,
N.Okimoto,
S.Hiraoka,
T.Nakahara,
R.Akasaka,
Y.Shiraishi,
N.Futatsugi,
Y.Mizutani-Koseki,
A.Kuroiwa,
M.Shirouzu,
S.Yokoyama,
M.Taiji,
S.Iseki,
D.M.Ornitz,
and
H.Koseki
(2009).
FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion.
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Nat Genet, 41,
289-298.
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W.M.Abdel-Rahman,
J.Kalinina,
S.Shoman,
S.Eissa,
M.Ollikainen,
O.Elomaa,
A.V.Eliseenkova,
R.Bützow,
M.Mohammadi,
and
P.Peltomäki
(2008).
Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous beta-catenin.
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Hum Mutat, 29,
390-397.
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R.Goetz,
A.Beenken,
O.A.Ibrahimi,
J.Kalinina,
S.K.Olsen,
A.V.Eliseenkova,
C.Xu,
T.A.Neubert,
F.Zhang,
R.J.Linhardt,
X.Yu,
K.E.White,
T.Inagaki,
S.A.Kliewer,
M.Yamamoto,
H.Kurosu,
Y.Ogawa,
M.Kuro-o,
B.Lanske,
M.S.Razzaque,
and
M.Mohammadi
(2007).
Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
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Mol Cell Biol, 27,
3417-3428.
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PDB codes:
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R.Sasisekharan,
R.Raman,
and
V.Prabhakar
(2006).
Glycomics approach to structure-function relationships of glycosaminoglycans.
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Annu Rev Biomed Eng, 8,
181-231.
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Y.Luo,
S.Ye,
M.Kan,
and
W.L.McKeehan
(2006).
Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb.
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J Cell Biochem, 97,
1241-1258.
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Y.Luo,
H.H.Cho,
and
W.L.McKeehan
(2003).
Biospecific extraction and neutralization of anticoagulant heparin with fibroblast growth factors (FGF).
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J Pharm Sci, 92,
2117-2127.
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M.Uzumcu,
S.D.Westfall,
K.A.Dirks,
and
M.K.Skinner
(2002).
Embryonic testis cord formation and mesonephric cell migration requires the phosphotidylinositol 3-kinase signaling pathway.
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Biol Reprod, 67,
1927-1935.
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P.Bellosta,
A.Iwahori,
A.N.Plotnikov,
A.V.Eliseenkova,
C.Basilico,
and
M.Mohammadi
(2001).
Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis.
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Mol Cell Biol, 21,
5946-5957.
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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
codes are
shown on the right.
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157 a.a.
