- Factor H
Complement factor H
PDB rendering based on 1haq.
Available structures PDB , , , , , , , , , , , , , , , , , , , , , , , , , Identifiers Symbols External IDs GeneCards: Gene Ontology Cellular component •
Biological process •
Sources: Amigo / QuickGO RNA expression pattern Orthologs Species Human Mouse Entrez Ensembl UniProt n/a RefSeq (mRNA) RefSeq (protein) Location (UCSC) PubMed search
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 a concentration of 500–800 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 and does not damage host tissue. Factor H regulates complement activation on self cells 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 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.
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 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. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCPs 12-13, 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 and CCPs 1-4 in complex with 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 19-20.
Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arrising 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 at an at-risk 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 interaction between factor H and heparin indicating a causal relationship between the SNP and disease. 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. 
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 and C3d binding.
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; Francisella tularensis; Haemophilus influenzae; Neisseria meningitidis; and Streptococcus pyogenes.
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- Kardys, I. et al. (2006). "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 (8): 1568–75. doi:10.1016/j.jacc.2005.11.076. PMID 16630992.
- Pío R, Elsasser TH, Martínez A, Cuttitta F (2002). "Identification, characterization, and physiological actions of factor H as an adrenomedullin binding protein present in human plasma". Microsc. Res. Tech. 57 (1): 23–7. doi:10.1002/jemt.10047. PMID 11921353.
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- GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
- GeneReviews/NCBI/NIH/UW entry on Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II
- OMIM entries on Atypical Hemolytic-Uremic Syndrome
- MeSH Complement+Factor+H
Proteins: complement system (C, L, A) Activators/enzymesEarlyMiddleLate Inhibitors Complement receptors Proteins: Globular proteins Serum globulinsOrosomucoid) · alpha-2 (alpha-2-Macroglobulin, Haptoglobin)Other Other globulins AlbuminsOthersee also disorders of globin and globulin proteins
B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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