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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{protein
{{PBB_Controls
| Name = Complement factor H
| update_page = yes
| caption = Complement H tetramer, Human
| require_manual_inspection = no
| image = 2g7i.jpg
| update_protein_box = yes
| width = 322
| update_summary = no
| update_citations = yes
}}
}}
{{Infobox_gene}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
'''Factor H''' is a member of the regulators of complement activation family and is a [[complement control protein]].  It is a large (155 kilodaltons), soluble [[glycoprotein]] that circulates in human [[Blood plasma|plasma]] (at typical concentrations of 200–300 [[micrograms]] per [[milliliter]]<ref>{{cite journal | vauthors = Sofat R, Mangione PP, Gallimore JR, Hakobyan S, Hughes TR, Shah T, Goodship T, D'Aiuto F, Langenberg C, Wareham N, Morgan BP, Pepys MB, Hingorani AD | title = Distribution and determinants of circulating complement factor H concentration determined by a high-throughput immunonephelometric assay | journal = Journal of Immunological Methods | volume = 390 | issue = 1-2 | pages = 63–73 | date = April 2013 | pmid = 23376722 | doi = 10.1016/j.jim.2013.01.009 }}</ref><ref name="Hakobyan-2008">{{cite journal | vauthors = Hakobyan S, Harris CL, Tortajada A, Goicochea de Jorge E, García-Layana A, Fernández-Robredo P, Rodríguez de Córdoba S, Morgan BP | title = Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration | journal = Investigative Ophthalmology & Visual Science | volume = 49 | issue = 5 | pages = 1983–90 | date = May 2008 | pmid = 18436830 | doi = 10.1167/iovs.07-1523 }}</ref><ref>{{cite journal | vauthors = Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M | title = Systemic complement activation in age-related macular degeneration | journal = PLoS One | volume = 3 | issue = 7 | pages = e2593 | date = July 2008 | pmid = 18596911 | doi = 10.1371/journal.pone.0002593 | pmc=2440421}}</ref>). Its principal function is to regulate the [[Alternative Pathway|alternative pathway]] of the [[complement system]], ensuring that the complement system is directed towards [[pathogens]] or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the [[complement Factor I|Factor I]] mediated [[C3b]] cleavage, and decay accelerating activity against the alternative pathway [[C3-convertase]], C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of [[bacteria]] or [[viruses]].  This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity.<ref name=":0">{{cite journal | vauthors = Herbert AP, Makou E, Chen ZA, Kerr H, Richards A, Rappsilber J, Barlow PN | title = Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement | journal = Journal of Immunology | volume = 195 | issue = 10 | pages = 4986–98 | date = November 2015 | pmid = 26459349 | pmc = 4635569 | doi = 10.4049/jimmunol.1501388 }}</ref>  The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to [[glycosaminoglycans]] (GAGs) and or [[sialic acid]]s that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.<ref name="pmid10904114">{{cite journal | vauthors = Pangburn MK | title = Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement | journal = Immunopharmacology | volume = 49 | issue = 1-2 | pages = 149–57 | date = August 2000 | pmid = 10904114 | doi = 10.1016/S0162-3109(00)80300-8 }}</ref><ref name="pmid15163532">{{cite journal | vauthors = Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P | title = The human complement factor H: functional roles, genetic variations and disease associations | journal = Molecular Immunology | volume = 41 | issue = 4 | pages = 355–67 | date = June 2004 | pmid = 15163532 | doi = 10.1016/j.molimm.2004.02.005 }}</ref>
{{GNF_Protein_box
 
| image = PBB_Protein_CFH_image.jpg
== Structure ==
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1haq.
 
  | PDB = {{PDB2|2uwn}}, {{PDB2|2v8e}}, {{PDB2|2jgx}}, {{PDB2|2jgw}}, {{PDB2|1hfi}}, {{PDB2|1hfh}}, {{PDB2|1hcc}}, {{PDB2|2qfh}}, {{PDB2|2g7i}}, {{PDB2|2bzm}}, {{PDB2|1haq}}
The molecule is made up of 20 [[complement control protein]] (CCP) modules (also referred to as Short Consensus Repeats or sushi domains) connected to one another by short linkers (of between three and eight [[amino acid]] residues) and arranged in an extended head to tail fashion.  Each of the CCP modules consists of around 60 [[amino acid]]s with four [[cysteine]] residues [[disulfide bond]]ed in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant [[tryptophan]] residue.  The CCP modules are numbered from 1-20 (from the N-terminus of the protein); CCPs 1-4 and CCPs 19-20 engage with [[C3b]] while CCPs 7 and CCPs 19-20 bind to GAGs and [[sialic acid]].<ref name="Schmidt-2008">{{cite journal | vauthors = Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrín D, Barlow PN | title = A new map of glycosaminoglycan and C3b binding sites on factor H | journal = Journal of Immunology | volume = 181 | issue = 4 | pages = 2610–9 | date = Aug 2008 | pmid = 18684951 | doi = 10.4049/jimmunol.181.4.2610 }}</ref> To date atomic structures have been determined for CCPs 1-3,<ref name="pmid18252712">{{cite journal | vauthors = Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrín D, Barlow PN | title = Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations | journal = The Journal of Biological Chemistry | volume = 283 | issue = 14 | pages = 9475–87 | date = Apr 2008 | pmid = 18252712 | pmc = 2276370 | doi = 10.1074/jbc.M709587200 }}</ref> CCP 5,<ref name="pmid1533152">{{cite journal | vauthors = Barlow PN, Norman DG, Steinkasserer A, Horne TJ, Pearce J, Driscoll PC, Sim RB, Campbell ID | title = Solution structure of the fifth repeat of factor H: a second example of the complement control protein module | journal = Biochemistry | volume = 31 | issue = 14 | pages = 3626–34 | date = Apr 1992 | pmid = 1533152 | pmc =  | doi = 10.1021/bi00129a011 }}</ref> CCP 7 (both 402H & 402Y),<ref name="pmid17360715">{{cite journal | vauthors = Herbert AP, Deakin JA, Schmidt CQ, Blaum BS, Egan C, Ferreira VP, Pangburn MK, Lyon M, Uhrín D, Barlow PN | title = Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism | journal = The Journal of Biological Chemistry | volume = 282 | issue = 26 | pages = 18960–8 | date = Jun 2007 | pmid = 17360715 | doi = 10.1074/jbc.M609636200 }}</ref> CCPs 10-11 and CCPs 11-12,<ref name="Makou-2012">{{cite journal | vauthors = Makou E, Mertens HD, Maciejewski M, Soares DC, Matis I, Schmidt CQ, Herbert AP, Svergun DI, Barlow PN | title = Solution structure of CCP modules 10-12 illuminates functional architecture of the complement regulator, factor H | journal = Journal of Molecular Biology | volume = 424 | issue = 5 | pages = 295–312 | date = Dec 2012 | pmid = 23017427 | doi = 10.1016/j.jmb.2012.09.013 }}</ref> CCPs 12-13,<ref name="pmid19835885">{{cite journal | vauthors = Schmidt CQ, Herbert AP, Mertens HD, Guariento M, Soares DC, Uhrin D, Rowe AJ, Svergun DI, Barlow PN | title = The central portion of factor H (modules 10-15) is compact and contains a structurally deviant CCP module | journal = Journal of Molecular Biology | volume = 395 | issue = 1 | pages = 105–22 | date = Jan 2010 | pmid = 19835885 | pmc = 2806952 | doi = 10.1016/j.jmb.2009.10.010 }}</ref> CCP 15, CCP 16,<ref name="pmid1829116">{{cite journal | vauthors = Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Campbell ID | title = Three-dimensional structure of a complement control protein module in solution | journal = Journal of Molecular Biology | volume = 219 | issue = 4 | pages = 717–25 | date = Jun 1991 | pmid = 1829116 | doi = 10.1016/0022-2836(91)90666-T }}</ref> CCPs 15-16,<ref name="pmid8331663">{{cite journal | vauthors = Barlow PN, Steinkasserer A, Norman DG, Kieffer B, Wiles AP, Sim RB, Campbell ID | title = Solution structure of a pair of complement modules by nuclear magnetic resonance | journal = Journal of Molecular Biology | volume = 232 | issue = 1 | pages = 268–84 | date = Jul 1993 | pmid = 8331663 | doi = 10.1006/jmbi.1993.1381 }}</ref> CCPs 18-20,<ref name="Morgan-2012">{{cite journal | vauthors = Morgan HP, Mertens HD, Guariento M, Schmidt CQ, Soares DC, Svergun DI, Herbert AP, Barlow PN, Hannan JP | title = Structural analysis of the C-terminal region (modules 18-20) of complement regulator factor H (FH) | journal = PLOS ONE | volume = 7 | issue = 2 | pages = e32187 | year = 2012 | pmid = 22389686 | pmc = 3289644 | doi = 10.1371/journal.pone.0032187 }}</ref> and CCPs 19-20.<ref name="pmid16533809">{{cite journal | vauthors = Herbert AP, Uhrín D, Lyon M, Pangburn MK, Barlow PN | title = Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure | journal = The Journal of Biological Chemistry | volume = 281 | issue = 24 | pages = 16512–20 | date = Jun 2006 | pmid = 16533809 | doi = 10.1074/jbc.M513611200 }}</ref><ref name="pmid16601698">{{cite journal | vauthors = Jokiranta TS, Jaakola VP, Lehtinen MJ, Pärepalo M, Meri S, Goldman A | title = Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome | journal = The EMBO Journal | volume = 25 | issue = 8 | pages = 1784–94 | date = Apr 2006 | pmid = 16601698 | pmc = 1440827 | doi = 10.1038/sj.emboj.7601052 }}</ref> The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate,<ref name="pmid17893204">{{cite journal | vauthors = Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrín D, Barlow PN, Sim RB, Day AJ, Lea SM | title = Structural basis for complement factor H linked age-related macular degeneration | journal = The Journal of Experimental Medicine | volume = 204 | issue = 10 | pages = 2277–83 | date = Oct 2007 | pmid = 17893204 | pmc = 2118454 | doi = 10.1084/jem.20071069 }}</ref> CCPs 1-4 in complex with C3b<ref name="pmid19503104">{{cite journal | vauthors = Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P | title = Structure of complement fragment C3b-factor H and implications for host protection by complement regulators | journal = Nature Immunology | volume = 10 | issue = 7 | pages = 728–33 | date = Jul 2009 | pmid = 19503104 | pmc = 2713992 | doi = 10.1038/ni.1755 }}</ref> and CCPs 19-20 in complex with [[C3d]] (that corresponds to the thioster domain of C3b)<ref name="Morgan-2011">{{cite journal | vauthors = Morgan HP, Schmidt CQ, Guariento M, Blaum BS, Gillespie D, Herbert AP, Kavanagh D, Mertens HD, Svergun DI, Johansson CM, Uhrín D, Barlow PN, Hannan JP | title = Structural basis for engagement by complement factor H of C3b on a self surface | journal = Nature Structural & Molecular Biology | volume = 18 | issue = 4 | pages = 463–70 | date = Apr 2011 | pmid = 21317894 | pmc = 3512577 | doi = 10.1038/nsmb.2018 }}</ref><ref name="Kajander-2011">{{cite journal | vauthors = Kajander T, Lehtinen MJ, Hyvärinen S, Bhattacharjee A, Leung E, Isenman DE, Meri S, Goldman A, Jokiranta TS | title = Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 7 | pages = 2897–902 | date = Feb 2011 | pmid = 21285368 | pmc = 3041134 | doi = 10.1073/pnas.1017087108 }}</ref> have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.<ref name="pmid11399083">{{cite journal | vauthors = Aslam M, Perkins SJ | title = Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling | journal = Journal of Molecular Biology | volume = 309 | issue = 5 | pages = 1117–38 | date = Jun 2001 | pmid = 11399083 | doi = 10.1006/jmbi.2001.4720 }}</ref>  Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19-20.<ref name="pmid11399083"/><ref name="pmid11414356">{{cite journal | vauthors = Kirkitadze MD, Barlow PN | title = Structure and flexibility of the multiple domain proteins that regulate complement activation | journal = Immunological Reviews | volume = 180 | issue =  | pages = 146–61 | date = Apr 2001 | pmid = 11414356 | doi = 10.1034/j.1600-065X.2001.1800113.x }}</ref>
  | Name = Complement factor H
 
| HGNCid = 4883
== Clinical significance ==
| Symbol = CFH
Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity.  Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections.  Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases.  It is not surprising therefore that [[mutations]] or [[single nucleotide polymorphisms]] (SNPs) in factor H often result in pathologies. Moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase [[virulence]].
| AltSymbols =; FH; FHL1; ARMD4; ARMS1; CFHL3; HF; HF1; HF2; HUS; MGC88246
 
| OMIM = 134370
=== Age-related macular degeneration ===
| ECnumber =
 
| Homologene = 20086
Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. [[Homozygous]] individuals have an approximately sevenfold increased chance of developing [[age-related macular degeneration]], while [[heterozygotes]] have a two-to-threefold increased likelihood of developing the disease.  This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and [[heparin]] indicating a causal relationship between the SNP and disease.<ref name="pmid17360715" /><ref name="pmid15870199">{{cite journal | vauthors = Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R | title = A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 20 | pages = 7227–32 | date = May 2005 | pmid = 15870199 | pmc = 1088171 | doi = 10.1073/pnas.0501536102 }}</ref>
| MGIid = 88385
 
| GeneAtlas_image1 = PBB_GE_CFH_215388_s_at_tn.png
Deletion of two adjacent genes with a high degree of homology to [[complement factor H]], named [[complement factor H-related 3]] and [[complement factor H-related 1]], protects against [[age-related macular degeneration]] because of reduced competition for binding of CFH to vascular surface binding sites.<ref name=HughesAE2006>{{cite journal | vauthors = Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U | title = A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration | journal = Nature Genetics | volume = 38 | issue = 10 | pages = 1173–7 | date = Oct 2006 | pmid = 16998489 | doi = 10.1038/ng1890 }}</ref><ref name=FritscheLG2010>{{cite journal | vauthors = Fritsche LG, Lauer N, Hartmann A, Stippa S, Keilhauer CN, Oppermann M, Pandey MK, Köhl J, Zipfel PF, Weber BH, Skerka C | title = An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD) | journal = Human Molecular Genetics | volume = 19 | issue = 23 | pages = 4694–704 | date = Dec 2010 | pmid = 20843825 | doi = 10.1093/hmg/ddq399 }}</ref>
| GeneAtlas_image2 = PBB_GE_CFH_213800_at_tn.png
 
| Function =  
=== Schizophrenia ===
| Component = {{GNF_GO|id=GO:0005615 |text = extracellular space}}  
 
  | Process = {{GNF_GO|id=GO:0006957 |text = complement activation, alternative pathway}}  
Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including [[schizophrenia]]. Recent studies indicated alterations in the [[complement system]], including hyperactivation of the [[alternative complement pathway]] in patients with schizophrenia. It was investigated functional single nucleotide polymorphisms (SNPs) of gene encoding factor H (CFH), and found CFH rs424535 (2783-526T >A) SNP was positively associated with schizophrenia, so rs424535*A minor allele of the CFH gene may represent a risk factor for schizophrenia.<ref name = "Boyajyan_2013">{{cite journal | vauthors = Boyajyan A, Ghazaryan H, Stepanyan A, Zakharyan R | title = Genetic polymorphisms of complement factor H in schizophrenia and ischemic stroke | journal = Mol. Immunol. | volume = 56 | issue = 3 | pages = 294 |date = December 2013 | doi = 10.1016/j.molimm.2013.05.154 }}</ref>
  | Orthologs = {{GNF_Ortholog_box
 
    | Hs_EntrezGene = 3075
=== Ischemic stroke ===
    | Hs_Ensembl = ENSG00000000971
It was found that rs800292(184G >A) SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke.<ref name = "Boyajyan_2013" />
    | Hs_RefseqProtein = NP_000177
    | Hs_RefseqmRNA = NM_000186
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 194887631
    | Hs_GenLoc_end = 194983257
    | Hs_Uniprot = P08603
    | Mm_EntrezGene = 12628
    | Mm_Ensembl =
    | Mm_RefseqmRNA = XM_001000306
    | Mm_RefseqProtein = XP_001000306
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr =
    | Mm_GenLoc_start =
    | Mm_GenLoc_end =
    | Mm_Uniprot =
  }}
}}


{{CMG}}
=== Atypical haemolytic uraemic syndrome ===


{{EH}}
[[Haemolytic uraemic syndrome]] (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, [[Complement factor I|factor I]] and [[membrane cofactor protein]]), with the factor H mutations being the most numerous.  These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt [[heparin]] (a model compound for glycosaminoglycans) and [[C3d]] (equivalent to the thioester domain of [[C3b]]) binding.<ref  name="pmid17548524">{{cite journal | vauthors = Atkinson JP, Goodship TH | title = Complement factor H and the hemolytic uremic syndrome | journal = The Journal of Experimental Medicine | volume = 204 | issue = 6 | pages = 1245–8 | date = Jun 2007 | pmid = 17548524 | pmc = 2118604 | doi = 10.1084/jem.20070664 }}</ref><ref>{{cite journal | vauthors = de Jorge EG, Macor P, Paixão-Cavalcante D, Rose KL, Tedesco F, Cook HT, Botto M, Pickering MC | title = The development of atypical hemolytic uremic syndrome depends on complement C5 | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 1 | pages = 137–45 | date = Jan 2011 | pmid = 21148255 | pmc = 3014042 | doi = 10.1681/ASN.2010050451 }}</ref>


'''Factor H''' is a member of the regulators of complement activation family and is a [[complement control protein]].  It is a large (155 kilodalton), soluble glycoprotein that circulates in human [[Blood plasma|plasma]] (at a concentration of 500-800 micrograms per mL). Its main job is to regulate the [[Alternative Pathway]] of the [[complement system]], ensuring that the complement system is directed towards [[pathogens]] and does not damage host tissue. Factor H regulates complement activation on self cells by possessing both cofactor activity for [[Factor I]] mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3 convertase, C3bBb. Factor H protects self cells from complement activation but not bacteria/viruses, in that it binds to [[glycosaminoglycans]] (GAGs) that are present on host cells but not pathogen cell surfaces.
=== Recruitment by pathogens ===
Given the central role of factor H in protecting cells from complement, it is not surprising that several important human [[pathogens]] have evolved mechanisms for recruiting factor H.  This recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence.  Pathogens that have been shown to recruit factor H include: [[Aspergillus]] spp.; [[Borrelia burgdorferi]]; [[B. duttonii]]; [[B. recurrentis]]; [[Candida albicans]];<ref name="pmid19850343">{{cite journal | vauthors = Luo S, Poltermann S, Kunert A, Rupp S, Zipfel PF | title = Immune evasion of the human pathogenic yeast Candida albicans: Pra1 is a Factor H, FHL-1 and plasminogen binding surface protein | journal = Molecular Immunology | volume = 47 | issue = 2-3 | pages = 541–50 | date = Dec 2009 | pmid = 19850343 | doi = 10.1016/j.molimm.2009.07.017 }}</ref> [[Francisella tularensis]]; [[Haemophilus influenzae]]; [[Neisseria meningitidis]]; [[Streptococcus pneumoniae|Streptococcus Pneumoniae]];<ref name=":0" /> and [[Streptococcus pyogenes]].
The Gram-negative bacterium ''B.burgdorferi'' has five Factor H binding proteins: CRASP-1, CRASP-2, CRASP-3, CRASP-4 and CRASP-5.<ref name="PF Zipfel, T Hallstrom and K Riesbeck 2013 152–160">{{cite journal | vauthors = Zipfel PF, Hallström T, Riesbeck K | title = Human complement control and complement evasion by pathogenic microbes--tipping the balance | journal = Molecular Immunology | volume = 56 | issue = 3 | pages = 152–60 | date = Dec 2013 | pmid = 23810413 | doi = 10.1016/j.molimm.2013.05.222 }}</ref> Each CRASP protein also binds plasminogen.<ref name="PF Zipfel, T Hallstrom and K Riesbeck 2013 152–160"/>


==Structure of Factor H==
== Interactions ==
The molecule is made up of 20 Complement Control Protein (CCP) modules (also referred to as Short Consensus Repeats or sushi domains) arranged head to tail.  Each of the CCP modules consists of around 60 [[amino acid]]s with four [[cysteine]] residues [[disulfide bond]]ed in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant [[tryptophan]] residue.  To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCP 15, CCP 16, CCPs 15-16, and CCPs 19-20.  The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate has also been determined.  Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.  Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or 19-20.


==Association with age-related macular degeneration==
Factor H has been shown to [[Protein-protein interaction|interact]] with [[Complement component 3]].<ref name="pmid9291131">{{cite journal | vauthors = Soames CJ, Sim RB | title = Interactions between human complement components factor H, factor I and C3b | journal = The Biochemical Journal | volume = 326 | issue = Pt 2 | pages = 553–61 | date = Sep 1997 | pmid = 9291131 | pmc = 1218704 | doi =  10.1042/bj3260553}}</ref><ref name="pmid11367533">{{cite journal | vauthors = Jokiranta TS, Westin J, Nilsson UR, Nilsson B, Hellwage J, Löfås S, Gordon DL, Ekdahl KN, Meri S | title = Complement C3b interactions studied with surface plasmon resonance technique | journal = International Immunopharmacology | volume = 1 | issue = 3 | pages = 495–506 | date = Mar 2001 | pmid = 11367533 | doi = 10.1016/S1567-5769(00)00042-4 }}</ref>
Recently is was discovered that about 35% of individuals carry at an at-risk [[single nucleotide polymorphism]] (SNP) in one or both copies of their factor H gene. [[Homozygous]] individuals have an approximately sevenfold increased chance of developing [[age-related macular degeneration]], while [[heterozygotes]] have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interactions between factor H and both [[C-reactive protein]] and [[heparin]] indicating a causal relationship between the SNP and disease.


==Association with atypical Haemolytic Uraemic Syndrome==
==Recombinant production==
[[Haemolytic uraemic syndrome]] (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, [[factor I]] and [[membrane cofactor protein]]), with the factor H mutations being the most numerous. These factor H mutations tend to congregate towards the C-terminus of factor H - a region responsible for discriminating self from non-self and have been shown to disrupt heparin and C3d binding.
Biologically active Factor H has been produced by [[Ralf Reski]] and coworkers in the [[moss bioreactor]],<ref name="pmid20723134">{{cite journal | vauthors = Büttner-Mainik A, Parsons J, Jérôme H, Hartmann A, Lamer S, Schaaf A, Schlosser A, Zipfel PF, Reski R, Decker EL | title = Production of biologically active recombinant human factor H in Physcomitrella | journal = Plant Biotechnology Journal | volume = 9 | issue = 3 | pages = 373–83 | date = Apr 2011 | pmid = 20723134 | doi = 10.1111/j.1467-7652.2010.00552.x }}</ref> in a process called [[molecular farming]]. Large quantities of biologically active human Factor H, potentially suitable for therapeutic purposes, were produced using a synthetic [[codon]]-optimised gene expressed in the [[yeast]] expression host, [[Pichia pastoris]].<ref name="Schmidt-2011">{{cite journal | vauthors = Schmidt CQ, Slingsby FC, Richards A, Barlow PN | title = Production of biologically active complement factor H in therapeutically useful quantities | journal = Protein Expression and Purification | volume = 76 | issue = 2 | pages = 254–63 | date = Apr 2011 | pmid = 21146613 | doi = 10.1016/j.pep.2010.12.002 | pmc = 4067574 }}</ref>


==Sources==
== References ==
* Pangburn, M.K. Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement. ''Immunopharmacology'' '''49''', 149-57 (2000).
{{Reflist|33em}}
* Aslam M. & Perkins S.J. Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling. ''J Mol Biol.'' '''309(5)''', 1117-38 (2001).
* Kirkitadze, M.D. & Barlow, P.N. Structure and flexibility of the multiple domain proteins that regulate complement activation. ''Immunol Rev'' '''180''', 146-61 (2001).
* Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. ''Proc Natl Acad Sci U S A'' '''102''', 7227-32.  (2005).
* Kardys, I. et al. A common polymorphism in the complement factor h gene is associated with increased risk of myocardial infarction the rotterdam study. ''J Am Coll Cardiol.'' '''47''', 1568-75. (2006).
* Herbert, A.P. et al. Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism. ''J Biol Chem.'' '''282(26)''', 18960-8. (2007).
* Hocking, H.G et al. Structure of the N-terminal region of complment factor H and conformational implications of disease-linked sequence variations. "J Biol Chem" Feb 5 Epub ahead of print (2008).


==Further reading==
== Further reading ==
{{refbegin | 1}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | volume = 25 | issue = 6 | pages = 683–93 | date = Jun 2011 | pmid = 21394116 | pmc = 3178140 | doi = 10.1038/eye.2011.37 }}
| citations =  
* {{cite journal | vauthors = Kardys I, Klaver CC, Despriet DD, Bergen AA, Uitterlinden AG, Hofman A, Oostra BA, Van Duijn CM, de Jong PT, Witteman JC | title = A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study | journal = Journal of the American College of Cardiology | volume = 47 | issue = 8 | pages = 1568–75 | date = Apr 2006 | pmid = 16630992 | doi = 10.1016/j.jacc.2005.11.076 }}
*{{cite journal | author=Pío R, Elsasser TH, Martínez A, Cuttitta F |title=Identification, characterization, and physiological actions of factor H as an adrenomedullin binding protein present in human plasma. |journal=Microsc. Res. Tech. |volume=57 |issue= 1 |pages= 23-7 |year= 2002 |pmid= 11921353 |doi= 10.1002/jemt.10047 }}
* {{cite journal | vauthors = Pío R, Elsasser TH, Martínez A, Cuttitta F | title = Identification, characterization, and physiological actions of factor H as an adrenomedullin binding protein present in human plasma | journal = Microscopy Research and Technique | volume = 57 | issue = 1 | pages = 23–7 | date = Apr 2002 | pmid = 11921353 | doi = 10.1002/jemt.10047 }}  
*{{cite journal | author=Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, ''et al.'' |title=The human complement factor H: functional roles, genetic variations and disease associations. |journal=Mol. Immunol. |volume=41 |issue= 4 |pages= 355-67 |year= 2004 |pmid= 15163532 |doi= 10.1016/j.molimm.2004.02.005 }}
* {{cite journal | vauthors = Walport MJ | title = Complement. First of two parts | journal = The New England Journal of Medicine | volume = 344 | issue = 14 | pages = 1058–66 | date = Apr 2001 | pmid = 11287977 | doi = 10.1056/NEJM200104053441406 }}
*{{cite journal | author=Walport MJ |title=Complement. First of two parts. |journal=N Engl J Med. |volume=344 |issue= 14 |pages= 1058-66 |year= 2001 |pmid= 11287977 }}
* {{cite journal | vauthors = Walport MJ | title = Complement. Second of two parts | journal = The New England Journal of Medicine | volume = 344 | issue = 15 | pages = 1140–4 | date = Apr 2001 | pmid = 11297706 | doi = 10.1056/NEJM200104123441506 }}
*{{cite journal | author=Walport MJ |title=Complement. Second of two parts. |journal=N Engl J Med. |volume=344 |issue= 15 |pages= 1140-4 |year= 2001 |pmid= 11297706 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1367/  GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome]
* [https://www.ncbi.nlm.nih.gov/books/NBK1425/  GeneReviews/NCBI/NIH/UW entry on Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II]
* [https://www.ncbi.nlm.nih.gov/omim/277400,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926  OMIM entries on Atypical Hemolytic-Uremic Syndrome] 
* {{MeshName|Complement+Factor+H}}
* {{MeshName|Complement+Factor+H}}


{{PDB Gallery|geneid=3075}}
{{Complement system}}
{{Complement system}}
{{Beta globulins}}
{{Beta globulins}}
[[Category:Complement system]]
[[Category:Complement system]]
[[Category:Immunology stubs]]
[[Category:Biochemistry stubs]]
{{WikiDoc Sources}}

Latest revision as of 15:19, 23 November 2018

Complement factor H
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Complement H tetramer, Human
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Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms per milliliter[1][2][3]). Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity.[4] The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.[5][6]

Structure

The molecule is made up of 20 complement control protein (CCP) modules (also referred to as Short Consensus Repeats or sushi domains) connected to one another by short linkers (of between three and eight amino acid residues) and arranged in an extended head to tail fashion. Each of the CCP modules consists of around 60 amino acids with four cysteine residues disulfide bonded in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant tryptophan residue. The CCP modules are numbered from 1-20 (from the N-terminus of the protein); CCPs 1-4 and CCPs 19-20 engage with C3b while CCPs 7 and CCPs 19-20 bind to GAGs and sialic acid.[7] To date atomic structures have been determined for CCPs 1-3,[8] CCP 5,[9] CCP 7 (both 402H & 402Y),[10] CCPs 10-11 and CCPs 11-12,[11] CCPs 12-13,[12] CCP 15, CCP 16,[13] CCPs 15-16,[14] CCPs 18-20,[15] and CCPs 19-20.[16][17] The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate,[18] CCPs 1-4 in complex with C3b[19] and CCPs 19-20 in complex with C3d (that corresponds to the thioster domain of C3b)[20][21] have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.[22] Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19-20.[22][23]

Clinical significance

Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms (SNPs) in factor H often result in pathologies. Moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence.

Age-related macular degeneration

Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. Homozygous individuals have an approximately sevenfold increased chance of developing age-related macular degeneration, while heterozygotes have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease.[10][24]

Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.[25][26]

Schizophrenia

Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the alternative complement pathway in patients with schizophrenia. It was investigated functional single nucleotide polymorphisms (SNPs) of gene encoding factor H (CFH), and found CFH rs424535 (2783-526T >A) SNP was positively associated with schizophrenia, so rs424535*A minor allele of the CFH gene may represent a risk factor for schizophrenia.[27]

Ischemic stroke

It was found that rs800292(184G >A) SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke.[27]

Atypical haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, factor I and membrane cofactor protein), with the factor H mutations being the most numerous. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin (a model compound for glycosaminoglycans) and C3d (equivalent to the thioester domain of C3b) binding.[28][29]

Recruitment by pathogens

Given the central role of factor H in protecting cells from complement, it is not surprising that several important human pathogens have evolved mechanisms for recruiting factor H. This recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence. Pathogens that have been shown to recruit factor H include: Aspergillus spp.; Borrelia burgdorferi; B. duttonii; B. recurrentis; Candida albicans;[30] Francisella tularensis; Haemophilus influenzae; Neisseria meningitidis; Streptococcus Pneumoniae;[4] and Streptococcus pyogenes. The Gram-negative bacterium B.burgdorferi has five Factor H binding proteins: CRASP-1, CRASP-2, CRASP-3, CRASP-4 and CRASP-5.[31] Each CRASP protein also binds plasminogen.[31]

Interactions

Factor H has been shown to interact with Complement component 3.[32][33]

Recombinant production

Biologically active Factor H has been produced by Ralf Reski and coworkers in the moss bioreactor,[34] in a process called molecular farming. Large quantities of biologically active human Factor H, potentially suitable for therapeutic purposes, were produced using a synthetic codon-optimised gene expressed in the yeast expression host, Pichia pastoris.[35]

References

  1. ↑ Sofat R, Mangione PP, Gallimore JR, Hakobyan S, Hughes TR, Shah T, Goodship T, D'Aiuto F, Langenberg C, Wareham N, Morgan BP, Pepys MB, Hingorani AD (April 2013). "Distribution and determinants of circulating complement factor H concentration determined by a high-throughput immunonephelometric assay". Journal of Immunological Methods. 390 (1–2): 63–73. doi:10.1016/j.jim.2013.01.009. PMID 23376722.
  2. ↑ Hakobyan S, Harris CL, Tortajada A, Goicochea de Jorge E, García-Layana A, Fernández-Robredo P, Rodríguez de Córdoba S, Morgan BP (May 2008). "Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration". Investigative Ophthalmology & Visual Science. 49 (5): 1983–90. doi:10.1167/iovs.07-1523. PMID 18436830.
  3. ↑ Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M (July 2008). "Systemic complement activation in age-related macular degeneration". PLoS One. 3 (7): e2593. doi:10.1371/journal.pone.0002593. PMC 2440421. PMID 18596911.
  4. ↑ 4.0 4.1 Herbert AP, Makou E, Chen ZA, Kerr H, Richards A, Rappsilber J, Barlow PN (November 2015). "Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement". Journal of Immunology. 195 (10): 4986–98. doi:10.4049/jimmunol.1501388. PMC 4635569. PMID 26459349.
  5. ↑ Pangburn MK (August 2000). "Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement". Immunopharmacology. 49 (1–2): 149–57. doi:10.1016/S0162-3109(00)80300-8. PMID 10904114.
  6. ↑ Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P (June 2004). "The human complement factor H: functional roles, genetic variations and disease associations". Molecular Immunology. 41 (4): 355–67. doi:10.1016/j.molimm.2004.02.005. PMID 15163532.
  7. ↑ Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrín D, Barlow PN (Aug 2008). "A new map of glycosaminoglycan and C3b binding sites on factor H". Journal of Immunology. 181 (4): 2610–9. doi:10.4049/jimmunol.181.4.2610. PMID 18684951.
  8. ↑ Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrín D, Barlow PN (Apr 2008). "Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations". The Journal of Biological Chemistry. 283 (14): 9475–87. doi:10.1074/jbc.M709587200. PMC 2276370. PMID 18252712.
  9. ↑ Barlow PN, Norman DG, Steinkasserer A, Horne TJ, Pearce J, Driscoll PC, Sim RB, Campbell ID (Apr 1992). "Solution structure of the fifth repeat of factor H: a second example of the complement control protein module". Biochemistry. 31 (14): 3626–34. doi:10.1021/bi00129a011. PMID 1533152.
  10. ↑ 10.0 10.1 Herbert AP, Deakin JA, Schmidt CQ, Blaum BS, Egan C, Ferreira VP, Pangburn MK, Lyon M, Uhrín D, Barlow PN (Jun 2007). "Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism". The Journal of Biological Chemistry. 282 (26): 18960–8. doi:10.1074/jbc.M609636200. PMID 17360715.
  11. ↑ Makou E, Mertens HD, Maciejewski M, Soares DC, Matis I, Schmidt CQ, Herbert AP, Svergun DI, Barlow PN (Dec 2012). "Solution structure of CCP modules 10-12 illuminates functional architecture of the complement regulator, factor H". Journal of Molecular Biology. 424 (5): 295–312. doi:10.1016/j.jmb.2012.09.013. PMID 23017427.
  12. ↑ Schmidt CQ, Herbert AP, Mertens HD, Guariento M, Soares DC, Uhrin D, Rowe AJ, Svergun DI, Barlow PN (Jan 2010). "The central portion of factor H (modules 10-15) is compact and contains a structurally deviant CCP module". Journal of Molecular Biology. 395 (1): 105–22. doi:10.1016/j.jmb.2009.10.010. PMC 2806952. PMID 19835885.
  13. ↑ Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Campbell ID (Jun 1991). "Three-dimensional structure of a complement control protein module in solution". Journal of Molecular Biology. 219 (4): 717–25. doi:10.1016/0022-2836(91)90666-T. PMID 1829116.
  14. ↑ Barlow PN, Steinkasserer A, Norman DG, Kieffer B, Wiles AP, Sim RB, Campbell ID (Jul 1993). "Solution structure of a pair of complement modules by nuclear magnetic resonance". Journal of Molecular Biology. 232 (1): 268–84. doi:10.1006/jmbi.1993.1381. PMID 8331663.
  15. ↑ Morgan HP, Mertens HD, Guariento M, Schmidt CQ, Soares DC, Svergun DI, Herbert AP, Barlow PN, Hannan JP (2012). "Structural analysis of the C-terminal region (modules 18-20) of complement regulator factor H (FH)". PLOS ONE. 7 (2): e32187. doi:10.1371/journal.pone.0032187. PMC 3289644. PMID 22389686.
  16. ↑ Herbert AP, Uhrín D, Lyon M, Pangburn MK, Barlow PN (Jun 2006). "Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure". The Journal of Biological Chemistry. 281 (24): 16512–20. doi:10.1074/jbc.M513611200. PMID 16533809.
  17. ↑ Jokiranta TS, Jaakola VP, Lehtinen MJ, Pärepalo M, Meri S, Goldman A (Apr 2006). "Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome". The EMBO Journal. 25 (8): 1784–94. doi:10.1038/sj.emboj.7601052. PMC 1440827. PMID 16601698.
  18. ↑ Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrín D, Barlow PN, Sim RB, Day AJ, Lea SM (Oct 2007). "Structural basis for complement factor H linked age-related macular degeneration". The Journal of Experimental Medicine. 204 (10): 2277–83. doi:10.1084/jem.20071069. PMC 2118454. PMID 17893204.
  19. ↑ Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P (Jul 2009). "Structure of complement fragment C3b-factor H and implications for host protection by complement regulators". Nature Immunology. 10 (7): 728–33. doi:10.1038/ni.1755. PMC 2713992. PMID 19503104.
  20. ↑ Morgan HP, Schmidt CQ, Guariento M, Blaum BS, Gillespie D, Herbert AP, Kavanagh D, Mertens HD, Svergun DI, Johansson CM, Uhrín D, Barlow PN, Hannan JP (Apr 2011). "Structural basis for engagement by complement factor H of C3b on a self surface". Nature Structural & Molecular Biology. 18 (4): 463–70. doi:10.1038/nsmb.2018. PMC 3512577. PMID 21317894.
  21. ↑ Kajander T, Lehtinen MJ, Hyvärinen S, Bhattacharjee A, Leung E, Isenman DE, Meri S, Goldman A, Jokiranta TS (Feb 2011). "Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement". Proceedings of the National Academy of Sciences of the United States of America. 108 (7): 2897–902. doi:10.1073/pnas.1017087108. PMC 3041134. PMID 21285368.
  22. ↑ 22.0 22.1 Aslam M, Perkins SJ (Jun 2001). "Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling". Journal of Molecular Biology. 309 (5): 1117–38. doi:10.1006/jmbi.2001.4720. PMID 11399083.
  23. ↑ Kirkitadze MD, Barlow PN (Apr 2001). "Structure and flexibility of the multiple domain proteins that regulate complement activation". Immunological Reviews. 180: 146–61. doi:10.1034/j.1600-065X.2001.1800113.x. PMID 11414356.
  24. ↑ Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R (May 2005). "A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (20): 7227–32. doi:10.1073/pnas.0501536102. PMC 1088171. PMID 15870199.
  25. ↑ Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U (Oct 2006). "A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration". Nature Genetics. 38 (10): 1173–7. doi:10.1038/ng1890. PMID 16998489.
  26. ↑ Fritsche LG, Lauer N, Hartmann A, Stippa S, Keilhauer CN, Oppermann M, Pandey MK, Köhl J, Zipfel PF, Weber BH, Skerka C (Dec 2010). "An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)". Human Molecular Genetics. 19 (23): 4694–704. doi:10.1093/hmg/ddq399. PMID 20843825.
  27. ↑ 27.0 27.1 Boyajyan A, Ghazaryan H, Stepanyan A, Zakharyan R (December 2013). "Genetic polymorphisms of complement factor H in schizophrenia and ischemic stroke". Mol. Immunol. 56 (3): 294. doi:10.1016/j.molimm.2013.05.154.
  28. ↑ Atkinson JP, Goodship TH (Jun 2007). "Complement factor H and the hemolytic uremic syndrome". The Journal of Experimental Medicine. 204 (6): 1245–8. doi:10.1084/jem.20070664. PMC 2118604. PMID 17548524.
  29. ↑ de Jorge EG, Macor P, Paixão-Cavalcante D, Rose KL, Tedesco F, Cook HT, Botto M, Pickering MC (Jan 2011). "The development of atypical hemolytic uremic syndrome depends on complement C5". Journal of the American Society of Nephrology. 22 (1): 137–45. doi:10.1681/ASN.2010050451. PMC 3014042. PMID 21148255.
  30. ↑ Luo S, Poltermann S, Kunert A, Rupp S, Zipfel PF (Dec 2009). "Immune evasion of the human pathogenic yeast Candida albicans: Pra1 is a Factor H, FHL-1 and plasminogen binding surface protein". Molecular Immunology. 47 (2–3): 541–50. doi:10.1016/j.molimm.2009.07.017. PMID 19850343.
  31. ↑ 31.0 31.1 Zipfel PF, Hallström T, Riesbeck K (Dec 2013). "Human complement control and complement evasion by pathogenic microbes--tipping the balance". Molecular Immunology. 56 (3): 152–60. doi:10.1016/j.molimm.2013.05.222. PMID 23810413.
  32. ↑ Soames CJ, Sim RB (Sep 1997). "Interactions between human complement components factor H, factor I and C3b". The Biochemical Journal. 326 (Pt 2): 553–61. doi:10.1042/bj3260553. PMC 1218704. PMID 9291131.
  33. ↑ Jokiranta TS, Westin J, Nilsson UR, Nilsson B, Hellwage J, Löfås S, Gordon DL, Ekdahl KN, Meri S (Mar 2001). "Complement C3b interactions studied with surface plasmon resonance technique". International Immunopharmacology. 1 (3): 495–506. doi:10.1016/S1567-5769(00)00042-4. PMID 11367533.
  34. ↑ Büttner-Mainik A, Parsons J, Jérôme H, Hartmann A, Lamer S, Schaaf A, Schlosser A, Zipfel PF, Reski R, Decker EL (Apr 2011). "Production of biologically active recombinant human factor H in Physcomitrella". Plant Biotechnology Journal. 9 (3): 373–83. doi:10.1111/j.1467-7652.2010.00552.x. PMID 20723134.
  35. ↑ Schmidt CQ, Slingsby FC, Richards A, Barlow PN (Apr 2011). "Production of biologically active complement factor H in therapeutically useful quantities". Protein Expression and Purification. 76 (2): 254–63. doi:10.1016/j.pep.2010.12.002. PMC 4067574. PMID 21146613.

Further reading

External links

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