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PDBsum entry 2odq
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References listed in PDB file
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Key reference
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Title
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The crystal structure of c2a, The catalytic fragment of classical pathway c3 and c5 convertase of human complement.
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Authors
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V.Krishnan,
Y.Xu,
K.Macon,
J.E.Volanakis,
S.V.Narayana.
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Ref.
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J Mol Biol, 2007,
367,
224-233.
[DOI no: ]
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PubMed id
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Abstract
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The multi-domain serine protease C2 provides the catalytic activity for the C3
and C5- convertases of the classical and lectin pathways of complement
activation. Formation of these convertases requires the Mg(2+)-dependent binding
of C2 to C4b, and the subsequent cleavage of C2 by C1s or MASP2, respectively.
The C-terminal fragment C2a consisting of a serine protease (SP) and a von
Willebrand factor type A (vWFA) domain, remains attached to C4b, forming the C3
convertase, C4b2a. Here, we present the crystal structure of Mg(2+)-bound C2a to
1.9 A resolution in comparison to its homolog Bb, the catalytic subunit of the
alternative pathway C3 convertase, C3bBb. Although the overall domain
arrangement of C2a is similar to Bb, there are certain structural differences.
Unexpectedly, the conformation of the metal ion-dependent adhesion site and the
position of the alpha7 helix of the vWFA domain indicate a co-factor-bound or
open conformation. The active site of the SP domain is in a zymogen-like
inactive conformation. On the basis of these structural features, we suggest a
model for the initial steps of C3 convertase assembly.
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Figure 3.
Figure 3. (a) Overall comparison of the vWFA domain of C2a
(magenta) and isolated vWFA domain of Bb (yellow). The magnesium
ion of C2a is shown in silver and that of Bb is shown in pink.
The N-terminal linker of C2a is shown in red and the disordered
α7 helix of Bb is shown by a yellow dotted line. (b) Stereo
view comparison of the α7 helix and its environment of C2a with
other known integrin I-domain “open” and “closed”
structures. C2 is in magenta; the ligand-free α2β1 I-domain
closed form is in yellow, the ligand-bound α2β1 I-domain is in
cyan and the Bb^C428–C435 mutant of Bb is in green. (c)
Stereo view of superposition of the α7 helix and its
environment of C2a (magenta) and Bb (yellow). The linker to the
SP domain of C2a shown in blue and that to Bb is shown in
green. The additional N terminus of C2a is shown in red. The
sugar molecule of C2a that is located at the domain interface
near the α7 helix is shown in white and labeled as NAG. The
magnesium ion of C2a is shown in silver and that of Bb is shown
in yellow. Figure 3. (a) Overall comparison of the vWFA
domain of C2a (magenta) and isolated vWFA domain of Bb (yellow).
The magnesium ion of C2a is shown in silver and that of Bb is
shown in pink. The N-terminal linker of C2a is shown in red and
the disordered α7 helix of Bb is shown by a yellow dotted line.
(b) Stereo view comparison of the α7 helix and its environment
of C2a with other known integrin I-domain “open” and
“closed” structures. C2 is in magenta; the ligand-free
α2β1 I-domain closed form is in yellow, the ligand-bound
α2β1 I-domain is in cyan and the Bb^C428–C435 mutant of Bb
is in green. (c) Stereo view of superposition of the α7 helix
and its environment of C2a (magenta) and Bb (yellow). The linker
to the SP domain of C2a shown in blue and that to Bb is shown in
green. The additional N terminus of C2a is shown in red. The
sugar molecule of C2a that is located at the domain interface
near the α7 helix is shown in white and labeled as NAG. The
magnesium ion of C2a is shown in silver and that of Bb is shown
in yellow.
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Figure 4.
Figure 4. (a) Stereo view of MIDAS motif comparison for
ligand-bound and ligand-free conformations. The metal ions are
shown in the same color as the main-chain ribbons, and the water
molecules are in blue. The ligand-free closed conformation, in
the presence of Mg^2+ for α2β1 I-domain (yellow) is superposed
on the ligand-bound open conformation of α2β1 Id-main (cyan)
and the ligand-free open-like conformation of C2a (magenta). A
Glu residue from the ligand collagen completes the coordination
of Mg in α2β1 I-domain open conformation. (b) Stereo view of a
detailed comparison of the MIDAS structures of C2a (magenta)
and Bb (yellow). The metal atom of C2a is shown as a silver
ball and that of Bb is shown as yellow ball. Continuous thin
lines indicate the metal coordination of C2a (magenta) and Bb
(yellow). Water molecules are shown in blue. Figure 4. (a)
Stereo view of MIDAS motif comparison for ligand-bound and
ligand-free conformations. The metal ions are shown in the same
color as the main-chain ribbons, and the water molecules are in
blue. The ligand-free closed conformation, in the presence of
Mg^2+ for α2β1 I-domain (yellow) is superposed on the
ligand-bound open conformation of α2β1 Id-main (cyan) and the
ligand-free open-like conformation of C2a (magenta). A Glu
residue from the ligand collagen completes the coordination of
Mg in α2β1 I-domain open conformation. (b) Stereo view of a
detailed comparison of the MIDAS structures of C2a (magenta) and
Bb (yellow). The metal atom of C2a is shown as a silver ball and
that of Bb is shown as yellow ball. Continuous thin lines
indicate the metal coordination of C2a (magenta) and Bb
(yellow). Water molecules are shown in blue.
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2007,
367,
224-233)
copyright 2007.
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