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PDBsum entry 2fdb
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Hormone/growth factor/transferase
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PDB id
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2fdb
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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 by which alternative splicing modulates the organizer activity of fgf8 in the brain.
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Authors
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S.K.Olsen,
J.Y.Li,
C.Bromleigh,
A.V.Eliseenkova,
O.A.Ibrahimi,
Z.Lao,
F.Zhang,
R.J.Linhardt,
A.L.Joyner,
M.Mohammadi.
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Ref.
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Genes Dev, 2006,
20,
185-198.
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PubMed id
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Abstract
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Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in
the mid-hindbrain region during development. Although the only difference
between these isoforms is the presence of an additional 11 amino acids at the N
terminus of FGF8b, these isoforms possess remarkably different abilities to
pattern the midbrain and anterior hindbrain. To reveal the structural basis by
which alternative splicing modulates the organizing activity of FGF8, we solved
the crystal structure of FGF8b in complex with the "c" splice isoform of FGF
receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also
characterized the receptor-binding specificity of FGF8a and FGF8b, the "b"
isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that
alternative splicing permits a single additional contact between phenylalanine
32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor
that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the
structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all
these receptors to levels characteristic of FGF8a. More importantly, analysis of
the mid-hindbrain patterning ability of the FGF8b(F32A) mutant in chick embryos
and murine midbrain explants shows that this mutation functionally converts
FGF8b to FGF8a. Moreover, our data suggest that the intermediate
receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b,
also account for the distinct patterning abilities of these two ligands. We also
show that the mode of FGF8 receptor-binding specificity is distinct from that of
other FGFs and provide the first biochemical evidence for a physiological
FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the
indispensable role of FGF8 in embryonic development, we show that the FGF8 mode
of receptor binding appeared as early as in nematodes and has been preserved
throughout evolution.
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