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PDBsum entry 2g7i
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Immune system
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PDB id
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2g7i
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References listed in PDB file
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Key reference
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Title
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Structure of complement factor h carboxyl-Terminus reveals molecular basis of atypical haemolytic uremic syndrome.
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Authors
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T.S.Jokiranta,
V.P.Jaakola,
M.J.Lehtinen,
M.Pärepalo,
S.Meri,
A.Goldman.
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Ref.
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EMBO J, 2006,
25,
1784-1794.
[DOI no: ]
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PubMed id
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Abstract
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Factor H (FH) is the key regulator of the alternative pathway of complement. The
carboxyl-terminal domains 19-20 of FH interact with the major opsonin C3b,
glycosaminoglycans, and endothelial cells. Mutations within this area are
associated with atypical haemolytic uremic syndrome (aHUS), a disease
characterized by damage to endothelial cells, erythrocytes, and kidney
glomeruli. The structure of recombinant FH19-20, solved at 1.8 A by X-ray
crystallography, reveals that the short consensus repeat domain 20 contains,
unusually, a short alpha-helix, and a patch of basic residues at its base. Most
aHUS-associated mutations either destabilize the structure or cluster in a
unique region on the surface of FH20. This region is close to, but distinct
from, the primary heparin-binding patch of basic residues. By mutating five
residues in this region, we show that it is involved, not in heparin, but in C3b
binding. Therefore, the majority of the aHUS-associated mutations on the surface
of FH19-20 interfere with the interaction between FH and C3b. This obviously
leads to impaired control of complement attack on plasma-exposed cell surfaces
in aHUS.
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Figure 1.
Figure 1 Electrostatic potential of FH19–20 on the surface in
two views 90° apart. Positive surface is blue and negative
red.
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Figure 2.
Figure 2 Tetrameric assembly of FH19–20, in stereo view. Each
of the monomers is in a different colour. The B and C monomer
amino-termini are on top (blue and purple), while the A and D
amino-termini are at the bottom (red and green). A schematic
view from the top is shown.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2006,
25,
1784-1794)
copyright 2006.
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