|Complement factor H|
|| Ortholog search: RCSB
|List of PDB id codes
||• heparan sulfate proteoglycan binding
||• extracellular space
||• innate immune response
|RNA expression pattern|
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, because it binds to 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 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 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 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 (a model compound for glycosaminoglycans) and C3d (equivalent to the thioester domain of 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 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.
Factor H has been shown to interact with Complement component 3.
Biologically active Factor H has been produced by Ralf Reski and coworkers in the moss bioreactor, 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.
- 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
- Medical Subject Headings (MeSH)