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PDBsum entry 3kzj
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Immune system
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PDB id
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3kzj
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References listed in PDB file
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Key reference
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Title
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Both domain 19 and domain 20 of factor h are involved in binding to complement c3b and c3d.
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Authors
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A.Bhattacharjee,
M.J.Lehtinen,
T.Kajander,
A.Goldman,
T.S.Jokiranta.
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Ref.
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Mol Immunol, 2010,
47,
1686-1691.
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PubMed id
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Abstract
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Factor H (FH) regulates the alternative pathway of complement in plasma and
mediates discrimination of cellular surfaces to alternative pathway activators
and non-activators. The carboxyl-terminal domains 19 and 20 of FH are essential
in target discrimination and are known to contain binding sites for the C3d part
of C3b, heparin, and endothelial cells. Mutations in FH19-20 are frequently
found in patients with atypical haemolytic uremic syndrome (aHUS). Most
aHUS-associated and some other mutations have been shown to lead to impaired
binding to C3d and C3b by the recombinant FH19-20 fragment. Most of these
mutated residues, such as R1203, are located close to each other in domain 20
but some, such as Q1139, are located in domain 19. We generated mutant proteins
Q1139A and R1203A of FH19-20 and showed that their binding to C3d and C3b was
clearly impaired. To show that the effects on C3d/C3b binding are due to direct
interactions rather than structural changes, we solved the X-ray crystal
structures of the R1203A and Q1139A mutant proteins at 1.65 and 2.0A,
respectively. Neither of the mutations caused any overall structural changes in
FH19-20. It is thus evident that Q1139 in domain 19 and R1203 in domain 20 are
directly involved in binding to the C3d part of C3b and therefore both the
domains are involved in the interaction with C3d and C3b. This explains why
several aHUS-associated FH mutations are found within domain 19 in addition to
domain 20.
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