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New page: left|200px<br /> <applet load="2ic4" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ic4" /> '''Solution structure of the His402 allotype o...
 
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[[Image:2ic4.gif|left|200px]]<br />
<applet load="2ic4" size="450" color="white" frame="true" align="right" spinBox="true"
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'''Solution structure of the His402 allotype of the Factor H SCR6-SCR7-SCR8 fragment'''<br />


==Overview==
==Solution structure of the His402 allotype of the Factor H SCR6-SCR7-SCR8 fragment==
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 muM 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.
<StructureSection load='2ic4' size='340' side='right'caption='[[2ic4]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2ic4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IC4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IC4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray solution scattering</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ic4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ic4 OCA], [https://pdbe.org/2ic4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ic4 RCSB], [https://www.ebi.ac.uk/pdbsum/2ic4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ic4 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CFAH_HUMAN CFAH_HUMAN] Genetic variations in CFH are associated with basal laminar drusen (BLD) [MIM:[https://omim.org/entry/126700 126700]; also known as drusen of Bruch membrane or cuticular drusen or grouped early adult-onset drusen. Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch membrane. Basal laminar drusen refers to an early adult-onset drusen phenotype that shows a pattern of uniform small, slightly raised yellow subretinal nodules randomly scattered in the macula. In later stages, these drusen often become more numerous, with clustered groups of drusen scattered throughout the retina. In time these small basal laminar drusen may expand and ultimately lead to a serous pigment epithelial detachment of the macula that may result in vision loss.  Defects in CFH are the cause of complement factor H deficiency (CFHD) [MIM:[https://omim.org/entry/609814 609814]. A disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3, and a decrease in other terminal complement components, indicating activation of the alternative complement pathway. It is associated with a number of renal diseases with variable clinical presentation and progression, including membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome.<ref>PMID:9312129</ref> <ref>PMID:10803850</ref> <ref>PMID:11170895</ref> <ref>PMID:11170896</ref> <ref>PMID:11158219</ref> <ref>PMID:12020532</ref> <ref>PMID:14978182</ref> <ref>PMID:16612335</ref>  Defects in CFH are a cause of susceptibility to hemolytic uremic syndrome atypical type 1 (AHUS1) [MIM:[https://omim.org/entry/235400 235400]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:14978182</ref> <ref>PMID:9551389</ref> <ref>PMID:10577907</ref> <ref>PMID:10762557</ref> <ref>PMID:11851332</ref> <ref>PMID:14583443</ref> <ref>PMID:12960213</ref> <ref>PMID:20513133</ref>  Genetic variation in CFH is associated with age-related macular degeneration type 4 (ARMD4) [MIM:[https://omim.org/entry/610698 610698]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid (known as drusen) that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:22019782</ref>
== Function ==
[https://www.uniprot.org/uniprot/CFAH_HUMAN CFAH_HUMAN] Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ic/2ic4_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ic4 ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
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]]
*[[Complement factor 3D structures|Complement factor 3D structures]]
 
== References ==
==About this Structure==
<references/>
2IC4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IC4 OCA].
__TOC__
 
</StructureSection>
==Reference==
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: Large Structures]]
[[Category: Clark, S.J.]]
[[Category: Clark SJ]]
[[Category: Day, A.J.]]
[[Category: Day AJ]]
[[Category: Fernando, A.N.]]
[[Category: Fernando AN]]
[[Category: Furtado, P.B.]]
[[Category: Furtado PB]]
[[Category: Gilbert, H.E.]]
[[Category: Gilbert HE]]
[[Category: Perkins, S.J.]]
[[Category: Perkins SJ]]
[[Category: Sim, R.B.]]
[[Category: Sim RB]]
[[Category: factor h]]
[[Category: homology modelling]]
[[Category: ultracentrifugation]]
[[Category: x-ray scattering]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:43:20 2007''

Latest revision as of 12:02, 21 February 2024

Solution structure of the His402 allotype of the Factor H SCR6-SCR7-SCR8 fragmentSolution structure of the His402 allotype of the Factor H SCR6-SCR7-SCR8 fragment

Structural highlights

2ic4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray solution scattering
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CFAH_HUMAN Genetic variations in CFH are associated with basal laminar drusen (BLD) [MIM:126700; also known as drusen of Bruch membrane or cuticular drusen or grouped early adult-onset drusen. Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch membrane. Basal laminar drusen refers to an early adult-onset drusen phenotype that shows a pattern of uniform small, slightly raised yellow subretinal nodules randomly scattered in the macula. In later stages, these drusen often become more numerous, with clustered groups of drusen scattered throughout the retina. In time these small basal laminar drusen may expand and ultimately lead to a serous pigment epithelial detachment of the macula that may result in vision loss. Defects in CFH are the cause of complement factor H deficiency (CFHD) [MIM:609814. A disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3, and a decrease in other terminal complement components, indicating activation of the alternative complement pathway. It is associated with a number of renal diseases with variable clinical presentation and progression, including membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome.[1] [2] [3] [4] [5] [6] [7] [8] Defects in CFH are a cause of susceptibility to hemolytic uremic syndrome atypical type 1 (AHUS1) [MIM:235400. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.[9] [10] [11] [12] [13] [14] [15] [16] Genetic variation in CFH is associated with age-related macular degeneration type 4 (ARMD4) [MIM:610698. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid (known as drusen) that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.[17]

Function

CFAH_HUMAN Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Ault BH, Schmidt BZ, Fowler NL, Kashtan CE, Ahmed AE, Vogt BA, Colten HR. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem. 1997 Oct 3;272(40):25168-75. PMID:9312129
  2. ↑ Sanchez-Corral P, Bellavia D, Amico L, Brai M, Rodriguez de Cordoba S. Molecular basis for factor H and FHL-1 deficiency in an Italian family. Immunogenetics. 2000 Apr;51(4-5):366-9. PMID:10803850
  3. ↑ Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet. 2001 Feb;68(2):478-84. Epub 2001 Jan 17. PMID:11170895 doi:S0002-9297(07)64099-3
  4. ↑ Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet. 2001 Feb;68(2):485-90. Epub 2001 Jan 17. PMID:11170896 doi:S0002-9297(07)64100-7
  5. ↑ Caprioli J, Bettinaglio P, Zipfel PF, Amadei B, Daina E, Gamba S, Skerka C, Marziliano N, Remuzzi G, Noris M. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol. 2001 Feb;12(2):297-307. PMID:11158219
  6. ↑ Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B. Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet. 2002 May 11;359(9318):1671-2. PMID:12020532 doi:10.1016/S0140-6736(02)08560-4
  7. ↑ Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004 Mar;15(3):787-95. PMID:14978182
  8. ↑ Licht C, Heinen S, Jozsi M, Loschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF. Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 2006 Jul;70(1):42-50. Epub 2006 Apr 12. PMID:16612335 doi:10.1038/sj.ki.5000269
  9. ↑ Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004 Mar;15(3):787-95. PMID:14978182
  10. ↑ Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998 Apr;53(4):836-44. PMID:9551389 doi:10.1111/j.1523-1755.1998.00824.x
  11. ↑ Ying L, Katz Y, Schlesinger M, Carmi R, Shalev H, Haider N, Beck G, Sheffield VC, Landau D. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am J Hum Genet. 1999 Dec;65(6):1538-46. PMID:10577907 doi:S0002-9297(07)63573-3
  12. ↑ Buddles MR, Donne RL, Richards A, Goodship J, Goodship TH. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am J Hum Genet. 2000 May;66(5):1721-2. PMID:10762557 doi:10.1086/302877
  13. ↑ Perkins SJ, Goodship TH. Molecular modelling of the C-terminal domains of factor H of human complement: a correlation between haemolytic uraemic syndrome and a predicted heparin binding site. J Mol Biol. 2002 Feb 15;316(2):217-24. PMID:11851332 doi:10.1006/jmbi.2001.5337
  14. ↑ Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet. 2003 Dec 15;12(24):3385-95. Epub 2003 Oct 28. PMID:14583443 doi:10.1093/hmg/ddg363
  15. ↑ Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, Lenk D, Bender BU, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Male DA, Franke G, Zipfel PF. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet. 2003 Sep;40(9):676-81. PMID:12960213
  16. ↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
  17. ↑ Raychaudhuri S, Iartchouk O, Chin K, Tan PL, Tai AK, Ripke S, Gowrisankar S, Vemuri S, Montgomery K, Yu Y, Reynolds R, Zack DJ, Campochiaro B, Campochiaro P, Katsanis N, Daly MJ, Seddon JM. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet. 2011 Oct 23;43(12):1232-6. doi: 10.1038/ng.976. PMID:22019782 doi:10.1038/ng.976
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