Factor H



Factor H is a member of the regulators of complement activation family and is a is_associated_with::complement control protein. It is a large (155 kilodaltons), soluble is_associated_with::glycoprotein that circulates in human plasma (at typical concentrations of 200–300 is_associated_with::micrograms per is_associated_with::milliliter ). Its principal function is to regulate the is_associated_with::Alternative Pathway of the is_associated_with::complement system, ensuring that the complement system is directed towards is_associated_with::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 is_associated_with::C3b cleavage, and decay accelerating activity against the alternative pathway is_associated_with::C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of is_associated_with::bacteria or is_associated_with::viruses, because it binds to is_associated_with::glycosaminoglycans (GAGs) that are generally present on host cells but not, normally, on pathogen surfaces.

Structure and function
The molecule is made up of 20 is_associated_with::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 is_associated_with::amino acid residues) and arranged in an extended head to tail fashion. Each of the CCP modules consists of around 60 is_associated_with::amino acids with four is_associated_with::cysteine residues is_associated_with::disulfide bonded in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant is_associated_with::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 is_associated_with::C3b while CCPs 7 and CCPs 19-20 bind to GAGs and is_associated_with::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 is_associated_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 19-20.

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 is_associated_with::mutations or is_associated_with::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 is_associated_with::virulence.

Age-related macular degeneration
Recently it was discovered that about 35% of individuals carry an at-risk SNP in one or both copies of their factor H gene. is_associated_with::Homozygous individuals have an approximately sevenfold increased chance of developing is_associated_with::age-related macular degeneration, while is_associated_with::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 is_associated_with::heparin indicating a causal relationship between the SNP and disease. Deletion of two adjacent genes with a high degree of homology to is_associated_with::complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against is_associated_with::age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.

Schizophrenia
Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including is_associated_with::schizophrenia. Recent studies indicated alterations in the is_associated_with::complement system, including hyperactivation of the is_associated_with::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.

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.

Atypical haemolytic uraemic syndrome
is_associated_with::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 is_associated_with::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 is_associated_with::heparin (a model compound for glycosaminoglycans) and is_associated_with::C3d (equivalent to the thioester domain of is_associated_with::C3b) binding.

Recruitment by pathogens
Given the central role of factor H in protecting cells from complement, it is not surprising that several important human is_associated_with::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: is_associated_with::Aspergillus spp.; is_associated_with::Borrelia burgdorferi; is_associated_with::B. duttonii; is_associated_with::B. recurrentis; is_associated_with::Candida albicans; is_associated_with::Francisella tularensis; is_associated_with::Haemophilus influenzae; is_associated_with::Neisseria meningitidis; and is_associated_with::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. Each CRASP protein also binds plasminogen.

Interactions
Factor H has been shown to interact with is_associated_with::Complement component 3.

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