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PDBsum entry 1h4b
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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, Dynamics, And hydrodynamics of the calcium-Bound cross-Reactive birch pollen allergen bet v 4 reveal a canonical monomeric two ef-Hand assembly with a regulatory function.
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Authors
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P.Neudecker,
J.Nerkamp,
A.Eisenmann,
A.Nourse,
T.Lauber,
K.Schweimer,
K.Lehmann,
S.Schwarzinger,
F.Ferreira,
P.Rösch.
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Ref.
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J Mol Biol, 2004,
336,
1141-1157.
[DOI no: ]
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PubMed id
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Abstract
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Birch pollinosis is one of the prevailing allergic diseases. In all, 5-20% of
birch pollinotics mount IgE antibodies against the minor birch pollen allergen
Bet v 4, a Ca2+-binding polcalcin. Due to IgE cross-reactivity among the
polcalcins these patients are polysensitized to various plant pollens.
Determination of the high-resolution structure of holo Bet v 4 by heteronuclear
NMR spectroscopy reveals a canonical two EF-hand assembly in the open
conformation with interhelical angles closely resembling holo calmodulin. The
polcalcin-specific amphipathic COOH-terminal alpha-helix covers only a part of
the hydrophobic groove on the molecular surface. Unlike the polcalcin Phl p 7
from timothy grass, which was recently shown to form a domain-swapped dimer, the
hydrodynamic parameters from NMR relaxation, NMR translational diffusion, and
analytical ultracentrifugation indicate that both apo and holo Bet v 4 are
predominantly monomeric, raising the question of the physiological and
immunological significance of the dimeric form of these polcalcins, whose
physiological function is still unknown. The reduced helicity and heat stability
in the CD spectra, the poor chemical shift dispersion of the NMR spectra, and
the slightly increased hydrodynamic radius of apo Bet v 4 indicate a reversible
structural transition upon Ca2+ binding, which explains the reduced IgE binding
capacity of apo Bet v 4. The remarkable structural similarity of holo Bet v 4
and holo Phl p 7 in spite of different oligomerization states explains the IgE
cross-reactivity and indicates that canonical monomers and domain-swapped dimers
may be of similar allergenicity. Together with the close structural homology to
calmodulin and the hydrophobic ligand binding groove this transition suggests a
regulatory function for Bet v 4.
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Figure 6.
Figure 6. Connolly surface of the lowest energy structure
of holo Bet v 4 colored according to hydrophobicity (top;
backbone yellow, hydrophobic residues green, hydrophilic
residues blue) or electrostatic potential (bottom; negative
potential red, positive potential blue). Opposite view as in
Figure 4 and Figure 5. The electric charge of the side-chain of
His48 depends on pH, at pH 6.0 it is predominantly protonated.
The COOH-terminal helix a[5] does not cover the hydrophobic
groove lined by negatively charged residues completely.
Formation of the domain-swapped dimer of holo Phl p 7 closes
this hydrophobic groove, resulting in a hydrophobic cavity which
is no longer solvent-accessible.[26.] The Figure was prepared
with InsightII 98.0 (Molecular Simulations Inc., San Diego, CA,
USA) and GRASP 1.2. [94.]
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Figure 8.
Figure 8. Backbone overlay of the average solution
structure of holo Bet v 4 (yellow) with the NH[2]-terminal
EF-hand of the first monomer (green) and the COOH-terminal
EF-hand of the second monomer (blue) of the crystal structure of
holo Phl p 7. Apart from the domain-swapping dimerization the
tertiary fold is almost identical. The overlay was performed
using Sybyl 6.5 (Tripos Inc., St. Louis, MO, USA).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
336,
1141-1157)
copyright 2004.
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