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PDBsum entry 3d5o
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Immune system
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PDB id
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3d5o
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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 recognition and functional activation of fcgammar by innate pentraxins.
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Authors
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J.Lu,
L.L.Marnell,
K.D.Marjon,
C.Mold,
T.W.Du clos,
P.D.Sun.
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Ref.
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Nature, 2008,
456,
989-992.
[DOI no: ]
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PubMed id
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Abstract
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Pentraxins are a family of ancient innate immune mediators conserved throughout
evolution. The classical pentraxins include serum amyloid P component (SAP) and
C-reactive protein, which are two of the acute-phase proteins synthesized in
response to infection. Both recognize microbial pathogens and activate the
classical complement pathway through C1q (refs 3 and 4). More recently, members
of the pentraxin family were found to interact with cell-surface Fcgamma
receptors (FcgammaR) and activate leukocyte-mediated phagocytosis. Here we
describe the structural mechanism for pentraxin's binding to FcgammaR and its
functional activation of FcgammaR-mediated phagocytosis and cytokine secretion.
The complex structure between human SAP and FcgammaRIIa reveals a diagonally
bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor
contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry
between SAP and FcgammaRIIa infers the requirement for multivalent pathogen
binding for receptor aggregation. Mutational and binding studies show that
pentraxins are diverse in their binding specificity for FcgammaR isoforms but
conserved in their recognition structure. The shared binding site for SAP and
IgG results in competition for FcgammaR binding and the inhibition of
immune-complex-mediated phagocytosis by soluble pentraxins. These results
establish antibody-like functions for pentraxins in the FcgammaR pathway,
suggest an evolutionary overlap between the innate and adaptive immune systems,
and have new therapeutic implications for autoimmune diseases.
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Figure 2.
Figure 2: Crystal structure of SAP–Fc bold gamma- RIIa
complex. a–c, The view is from the face (a) and sides (b,
c) of SAP; in c only the receptor contact A and C subunits are
highlighted. The five SAP subunits are shown in yellow with
ridge helices in red, and Fc  RIIa
is coloured blue. The interface is represented by a molecular
surface in green. The Ca^2+-binding and ligand-binding sites on
SAP are highlighted in magenta. d, Comparison between the free
(green) and receptor-bound (yellow) SAP, and between the free
(wheat) and SAP-bound (blue) Fc RIIa
structures. For clarity, only the A subunit is shown from the
superposition of SAP pentamer. The BC loop (residues 28–35) of
the D1 domain is indicated.
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Figure 3.
Figure 3: The binding interfaces between SAP and Fc bold
gamma-RIIa.
a, The interface between the D1 domain of Fc RIIa
(blue and magenta) and the A subunit of SAP (yellow and green)
is shown, with participating side residues shown as sticks.
Hydrogen-bond interactions are represented by red dashed lines.
b, The interface between the D2 domain of Fc RIIa
and the C subunit of SAP.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nature
(2008,
456,
989-992)
copyright 2008.
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