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). 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 either different conformations with lower or higher activity. 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.
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. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCPs 10-11 and CCPs 11-12, CCPs 12-13, CCP 15, CCP 16, CCPs 15-16, CCPs 18-20, and CCPs 19-20. The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate, CCPs 1-4 in complex with C3b and CCPs 19-20 in complex with C3d (that corresponds to the thioster domain of C3b) 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. 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.
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.
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.
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.
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.
^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. PMID23376722.
^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. PMID18436830.
^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. PMID10904114.
^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. PMID15163532.
^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. PMID18684951.
^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. PMID1533152.
^ abHerbert 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. PMID17360715.
^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. PMID23017427.
^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. PMID1829116.
^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. PMID8331663.
^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. PMID16533809.
^ abAslam 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. PMID11399083.
^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. PMID16998489.
^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. PMID20843825.
^ abBoyajyan 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.
^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. PMID11367533.
^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. PMID20723134.
^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. PMID21146613.
Kardys I, Klaver CC, Despriet DD, Bergen AA, Uitterlinden AG, Hofman A, Oostra BA, Van Duijn CM, de Jong PT, Witteman JC (Apr 2006). "A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study". Journal of the American College of Cardiology. 47 (8): 1568–75. doi:10.1016/j.jacc.2005.11.076. PMID16630992.
Pío R, Elsasser TH, Martínez A, Cuttitta F (Apr 2002). "Identification, characterization, and physiological actions of factor H as an adrenomedullin binding protein present in human plasma". Microscopy Research and Technique. 57 (1): 23–7. doi:10.1002/jemt.10047. PMID11921353.