2ic4: Difference between revisions
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==Overview== | ==Overview== | ||
Factor H (FH) is a major complement control protein in serum. The seventh | Factor H (FH) is a major complement control protein in serum. The seventh short complement regulator (SCR-7) domain of the 20 in FH is associated with age-related macular degeneration through a Tyr402His polymorphism. The recombinant SCR-6/8 domains containing either His402 or Tyr402 and their complexes with a heparin decasaccharide were studied by analytical ultracentrifugation and X-ray scattering. The sedimentation coefficient is concentration dependent, giving a value of 2.0 S at zero concentration and a frictional ratio f/f(o) of 1.2 for both allotypes. The His402 allotype showed a slightly greater self-association than the Tyr402 allotype, and small amounts of dimeric SCR-6/8 were found for both allotypes in 50 mM, 137 mM and 250 mM NaCl buffers. Sedimentation equilibrium data were interpreted in terms of a monomer-dimer equilibrium with a dissociation constant of 40 microM for the His402 form. The Guinier radius of gyration R(G) of 3.1-3.3 nm and the R(G)/R(O) ratio of 2.0-2.1 showed that SCR-6/8 is relatively extended in solution. The distance distribution function P(r) showed a maximum dimension of 10 nm, which is less than the length expected for a linear domain arrangement. The constrained scattering and sedimentation modelling of FH SCR-6/8 showed that bent SCR arrangements fit the data better than linear arrangements. Previously identified heparin-binding residues were exposed on the outside curvature of this bent domain structure. Heparin caused the formation of a more linear structure, possibly by binding to residues in the linker. It was concluded that the His402 allotype may self-associate more readily than the Tyr402 allotype, SCR-6/8 is partly responsible for the folded-back structure of intact FH, and SCR-6/8 changes conformation upon heparin binding. | ||
==Disease== | |||
Known diseases associated with this structure: Complement factor H deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Factor H and factor H-like 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Hemolytic-uremic syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Macular degeneration, age-related, 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]] | |||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
Associative and | Associative and structural properties of the region of complement factor H encompassing the Tyr402His disease-related polymorphism and its interactions with heparin., Fernando AN, Furtado PB, Clark SJ, Gilbert HE, Day AJ, Sim RB, Perkins SJ, J Mol Biol. 2007 Apr 27;368(2):564-81. Epub 2007 Feb 22. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17362990 17362990] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Clark, S | [[Category: Clark, S J.]] | ||
[[Category: Day, A | [[Category: Day, A J.]] | ||
[[Category: Fernando, A | [[Category: Fernando, A N.]] | ||
[[Category: Furtado, P | [[Category: Furtado, P B.]] | ||
[[Category: Gilbert, H | [[Category: Gilbert, H E.]] | ||
[[Category: Perkins, S | [[Category: Perkins, S J.]] | ||
[[Category: Sim, R | [[Category: Sim, R B.]] | ||
[[Category: factor h]] | [[Category: factor h]] | ||
[[Category: homology modelling]] | [[Category: homology modelling]] | ||
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[[Category: x-ray scattering]] | [[Category: x-ray scattering]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:51:06 2008'' | ||
Revision as of 18:51, 21 February 2008
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Solution structure of the His402 allotype of the Factor H SCR6-SCR7-SCR8 fragment
OverviewOverview
Factor H (FH) is a major complement control protein in serum. The seventh short complement regulator (SCR-7) domain of the 20 in FH is associated with age-related macular degeneration through a Tyr402His polymorphism. The recombinant SCR-6/8 domains containing either His402 or Tyr402 and their complexes with a heparin decasaccharide were studied by analytical ultracentrifugation and X-ray scattering. The sedimentation coefficient is concentration dependent, giving a value of 2.0 S at zero concentration and a frictional ratio f/f(o) of 1.2 for both allotypes. The His402 allotype showed a slightly greater self-association than the Tyr402 allotype, and small amounts of dimeric SCR-6/8 were found for both allotypes in 50 mM, 137 mM and 250 mM NaCl buffers. Sedimentation equilibrium data were interpreted in terms of a monomer-dimer equilibrium with a dissociation constant of 40 microM for the His402 form. The Guinier radius of gyration R(G) of 3.1-3.3 nm and the R(G)/R(O) ratio of 2.0-2.1 showed that SCR-6/8 is relatively extended in solution. The distance distribution function P(r) showed a maximum dimension of 10 nm, which is less than the length expected for a linear domain arrangement. The constrained scattering and sedimentation modelling of FH SCR-6/8 showed that bent SCR arrangements fit the data better than linear arrangements. Previously identified heparin-binding residues were exposed on the outside curvature of this bent domain structure. Heparin caused the formation of a more linear structure, possibly by binding to residues in the linker. It was concluded that the His402 allotype may self-associate more readily than the Tyr402 allotype, SCR-6/8 is partly responsible for the folded-back structure of intact FH, and SCR-6/8 changes conformation upon heparin binding.
DiseaseDisease
Known diseases associated with this structure: Complement factor H deficiency OMIM:[134370], Factor H and factor H-like 1 OMIM:[134370], Hemolytic-uremic syndrome OMIM:[134370], Macular degeneration, age-related, 4 OMIM:[134370], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[134370]
About this StructureAbout this Structure
2IC4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Associative and structural properties of the region of complement factor H encompassing the Tyr402His disease-related polymorphism and its interactions with heparin., Fernando AN, Furtado PB, Clark SJ, Gilbert HE, Day AJ, Sim RB, Perkins SJ, J Mol Biol. 2007 Apr 27;368(2):564-81. Epub 2007 Feb 22. PMID:17362990
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