From Wikipedia, the free encyclopedia Factor H
Factor H
Complement factor H RefSeq NM_000186.3 NM_009888.3
(mRNA)
RefSeq NP_000177.2 NP_034018.2
(protein)
Location Chr 1: Chr 1:
(UCSC) 196.62 – 196.72 Mb 141.98 – 142.08 Mb
PubMed [2] [3]
search
Factor H is a member of the regulators of complement ac-
tivation family and is a complement control protein. It is
a large (155 kilodaltons), soluble glycoprotein that circu-
lates in human plasma (at a concentration of 500–800 mi-
PDB rendering based on 1haq. crograms per milliliter). Its principal function is to regu-
late the Alternative Pathway of the complement system,
Identifiers ensuring that the complement system is directed to-
wards pathogens and does not damage host tissue. Factor
Symbols CFH; AHUS1; AMBP1; ARMD4; ARMS1; CFHL3;
H regulates complement activation on self cells by pos-
FH; FHL1; HF; HF1; HF2; HUS; MGC88246
sessing both cofactor activity for the Factor I mediated
External OMIM: 134370 MGI: 88385 HomoloGene: 20086 C3b cleavage, and decay accelerating activity against the
IDs GeneCards: CFH Gene alternative pathway C3 convertase, C3bBb. Factor H pro-
tects self cells from complement activation but not bacte-
RNA expression pattern ria/viruses, in that it binds to glycosaminoglycans (GAGs)
that are present on host cells but not pathogen cell sur-
faces.[1][2]
Structure
The molecule is made up of 20 complement control pro-
tein (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 al-
most invariant tryptophan residue. To date atomic struc-
tures have been determined for CCPs 1-3[3], CCP 5,[4] CCP
7 (both 402H & 402Y)[5], CCPs 12-13,[6] CCP 15, CCP 16,[7]
CCPs 15-16,[8] and CCPs 19-20.[9][10] The atomic structure
for CCPs 6-8 (402H) bound to the GAG mimic sucrose octa-
sulfate[11] and CCPs 1-4 in complex with C3b[12] have also
More reference expression data been determined. Although an atomic resolution struc-
ture for intact factor H has not yet been determined, low
Orthologs
resolution techniques indicate that it may be bent back in
Species Human Mouse solution.[13] Information available to date indicates that
CCP modules 1-4 is responsible for the cofactor and decay
Entrez 3075 12628
acceleration activities of factor H, whereas self/non-self
Ensembl ENSG00000000971 ENSMUSG00000026365 discrimination occurs predominantly through GAG bind-
ing to CCP modules 7 and/or 19-20.[13][14]
UniProt P08603 n/a
1
From Wikipedia, the free encyclopedia Factor H
Clinical significance Borrelia burgdorferi; B. duttonii; B. recurrentis; Candida
albicans; Francisella tularensis; Haemophilus influenzae;
Due to the central role that factor H plays in the regu- Neisseria meningitidis; and Streptococcus pyogenes.
lation of complement, there are a number of clinical im-
plications arrising from aberrant factor H activity. Over-
active factor H may result in reduced complement ac-
Interactions
tivity on pathogenic cells - increasing susceptibility to Factor H has been shown to interact with Complement
microbial infections. Underactive factor H may result in component 3.[19][20]
increased complement activity on healthy host cells -
resulting in autoimmune diseases. It is not surprising
therefore that mutations or single nucleotide polymor-
Recombinant production
phisms (SNPs) in factor H often result in pathologies. Biologically active Factor H has been produced by Ralf
Moreover the complement inhibitory activities of factor Reski and coworkers in the moss bioreactor [21], in a
H, and other complement regulators, are often used by process called molecular farming.
pathogens to increase virulence.
Age-related macular degeneration
References
[1] Pangburn MK (August 2000). "Host recognition and
Recently it was discovered that about 35% of individuals
target differentiation by factor H, a regulator of the
carry an at-risk SNP in one or both copies of their factor
alternative pathway of complement".
H gene. Homozygous individuals have an approximately
Immunopharmacology 49 (1–2): 149–57. doi:10.1016/
sevenfold increased chance of developing age-related
S0162-3109(00)80300-8. PMID 10904114.
macular degeneration, while heterozygotes have a two-
[2] Rodríguez de Córdoba S, Esparza-Gordillo J,
to-threefold increased likelihood of developing the dis-
Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-
ease. This SNP, located in CCP module 7 of factor H, has
Corral P (June 2004). "The human complement
been shown to affect the interaction between factor H
factor H: functional roles, genetic variations and
and heparin indicating a causal relationship between the
disease associations". Mol. Immunol. 41 (4): 355–67.
SNP and disease.[15][5] Deletion of two adjacent genes
doi:10.1016/j.molimm.2004.02.005. PMID 15163532.
with a high degree of homology to complement factor H,
[3] Hocking HG, Herbert AP, Kavanagh D, Soares DC,
named complement factor H-related 3 and complement
Ferreira VP, Pangburn MK, Uhrín D, Barlow PN
factor H-related 1, protects against age-related macular
(April 2008). "Structure of the N-terminal Region of
degeneration because of reduced competition for bind-
Complement Factor H and Conformational
ing of CFH to vascular surface binding sites.[16] [17]
Implications of Disease-linked Sequence
Variations". J. Biol. Chem. 283 (14): 9475–87.
Atypical haemolytic uraemic syndrome doi:10.1074/jbc.M709587200. PMC 2276370.
Haemolytic uraemic syndrome (HUS) is a disease associ- PMID 18252712.
ated with microangiopathic haemolytic anemia, throm- http://www.pubmedcentral.nih.gov/
bocytopenia and acute renal failure. A rare subset of this articlerender.fcgi?tool=pmcentrez&artid=2276370.
disease (referred to as atypical haemolytic uraemic syn- [4] Barlow PN, Norman DG, Steinkasserer A, Horne TJ,
drome, aHUS), has been strongly linked to mutations in Pearce J, Driscoll PC, Sim RB, Campbell ID. (1992).
genes of the complement system (including factor H, fac- "Solution structure of the fifth repeat of factor H: a
tor I and membrane cofactor protein), with the factor H second example of the complement control protein
mutations being the most numerous. These factor H mu- module". Biochemistry. 31 (14): 3626–34.
tations tend to congregate towards the C-terminus of fac- doi:10.1021/bi00129a011. PMID 1533152.
tor H—a region responsible for discriminating self from [5] ^ Herbert AP, Deakin JA, Schmidt CQ, Blaum BS,
non-self and have been shown to disrupt heparin and C3d Egan C, Ferreira VP, Pangburn MK, Lyon M, Uhrín
binding.[18] D, Barlow PN (June 2007). "Structure shows that a
glycosaminoglycan and protein recognition site in
Recruitment by pathogens factor H is perturbed by age-related macular
Given the central role of factor H in protecting cells from degeneration-linked single nucleotide
complement, it is not surprising that several important polymorphism". J. Biol. Chem. 282 (26): 18960–8.
human pathogens have evolved mechanisms for recruit- doi:10.1074/jbc.M609636200. PMID 17360715.
ing factor H. This recruitment of factor H by pathogens [6] Schmidt CQ, Herbert AP, Mertens HD, Guariento M,
provides significant resistance to complement attack, Soares DC, Uhrin D, Rowe AJ, Svergun DI, Barlow
and therefore increased virulence. Pathogens that have PN. (2010). "The Central Portion of Factor H
been shown to recruit factor H include: Aspergillus spp.; (Modules 10–15) Is Compact and Contains a
2
From Wikipedia, the free encyclopedia Factor H
Structurally Deviant CCP Module". J Mol Biol. 395 regulate complement activation". Immunol. Rev.
(1): 105–22. doi:10.1016/j.jmb.2009.10.010. 180:
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PMC 2806952. PMID 19835885. j.1600-065X.2001.1800113.x. PMID 11414356.
http://www.pubmedcentral.nih.gov/ [15] Hageman GS, Anderson DH, Johnson LV, Hancox LS,
articlerender.fcgi?tool=pmcentrez&artid=2806952. Taiber AJ, Hardisty LI, Hageman JL, Stockman HA,
[7] Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G,
Campbell ID. (1991). "Three-dimensional structure Russell SR, Klaver CC, Barbazetto I, Chang S,
of a complement control protein module in Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh
solution". J Mol Biol. 219 (4): 717–25. doi:10.1016/ AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean
0022-2836(91)90666-T. PMID 1829116. M, Allikmets R (May 2005). "A common haplotype
[8] Barlow PN, Steinkasserer A, Norman DG, Kieffer B, in the complement regulatory gene factor H (HF1/
Wiles AP, Sim RB, Campbell ID. (1993). "Solution CFH) predisposes individuals to age-related
structure of a pair of complement modules by macular degeneration". Proc. Natl. Acad. Sci. U.S.A.
nuclear magnetic resonance". J Mol Biol. 232 (1): 102 (20): 7227–32. doi:10.1073/pnas.0501536102.
268–84. doi:10.1006/jmbi.1993.1381. PMID 8331663. PMC 1088171. PMID 15870199.
[9] Herbert AP, Uhrín D, Lyon M, Pangburn MK, Barlow http://www.pubmedcentral.nih.gov/
PN. (march 2006). "Disease-associated sequence articlerender.fcgi?tool=pmcentrez&artid=1088171.
variations congregate in a polyanion recognition [16] Hughes, Anne E; Orr, Nick; Esfandiary, Hossein;
patch on human factor H revealed in three- Diaz-Torres, Martha; Goodship, Timothy;
dimensional structure". J Biol Chem. 281 (24): Chakravarthy, Usha (2006). "A common CFH
16512–20. doi:10.1074/jbc.M513611200. haplotype, with deletion of CFHR1 and CFHR3, is
PMID 16533809. associated with lower risk of age-related macular
[10] Jokiranta TS, Jaakola VP, Lehtinen MJ, Pärepalo M, degeneration". Nature Genetics 38 (10): 1173–1177.
Meri S, Goldman A. (April 2006). "Structure of doi:10.1038/ng1890. PMID 16998489.
complement factor H carboxyl-terminus reveals [17] Fritsche, L. G.; Lauer, N.; Hartmann, A.; Stippa, S.;
molecular basis of atypical haemolytic uremic Keilhauer, C. N.; Oppermann, M.; Pandey, M. K.;
syndrome". EMBO J. 25 (8): 1784–94. doi:10.1038/ Kohl, J. et al. (2010). "An imbalance of human
sj.emboj.7601052. PMC 1440827. PMID 16601698. complement regulatory proteins CFHR1, CFHR3
http://www.pubmedcentral.nih.gov/ and factor H influences risk for age-related
articlerender.fcgi?tool=pmcentrez&artid=1440827. macular degeneration (AMD)". Human Molecular
[11] Prosser BE, Johnson S, Roversi P, Herbert AP, Genetics 19 (23): 4694–4704. doi:10.1093/hmg/
Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, ddq399. PMID 20843825.
Uhrín D, Barlow PN, Sim RB, Day AJ, Lea SM. [18] Atkinson JP, Goodship TH (June 2007).
(September 2007). "Structural basis for "Complement factor H and the hemolytic uremic
complement factor H–linked age-related macular syndrome". J. Exp. Med. 204 (6): 1245–8. doi:10.1084/
degeneration". J Exp Med. 204 (10): 2277–83. jem.20070664. PMC 2118604. PMID 17548524.
doi:10.1084/jem.20071069. PMC 2118454. http://www.pubmedcentral.nih.gov/
PMID 17893204. articlerender.fcgi?tool=pmcentrez&artid=2118604.
http://www.pubmedcentral.nih.gov/ [19] Soames, C J; Sim R B (Sep. 1997). "Interactions
articlerender.fcgi?tool=pmcentrez&artid=2118454. between human complement components factor H,
[12] Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros factor I and C3b". Biochem. J. (ENGLAND) 326 ( Pt 2)
P. (2009). "Structure of C3b-factor H and (Pt 2): 553–61. ISSN 0264-6021. PMC 1218704.
implications for host protection by complement PMID 9291131.
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articlerender.fcgi?tool=pmcentrez&artid=2713992. Hellwage J, Löfås S, Gordon D L, Ekdahl K N, Meri S
[13] ^ Aslam M, Perkins SJ. (June 2001). "Folded-back (Mar. 2001). "Complement C3b interactions studied
solution structure of monomeric factor H of human with surface plasmon resonance technique". Int.
complement by synchrotron X-ray and neutron Immunopharmacol. (Netherlands) 1 (3): 495–506.
scattering, analytical ultracentrifugation and doi:10.1016/S1567-5769(00)00042-4.
constrained molecular modelling". J Mol Biol. 309 ISSN 1567-5769. PMID 11367533.
(25): 1117–1138. doi:10.1006/jmbi.2001.4720. [21] Büttner-Mainik, A., J. Parsons, H. Jérome, A.
PMID 11399083. Hartmann, S. Lamer, A. Schaaf, A. Schlosser, P.F.
[14] Kirkitadze MD, Barlow PN (April 2001). "Structure Zipfel, R. Reski, E.L. Decker (2011): Production of
and flexibility of the multiple domain proteins that biologically active recombinant human factor H in
3
From Wikipedia, the free encyclopedia Factor H
Physcomitrella. Plant Biotechnology Journal, doi: • Walport MJ; Rosen, Fred S.; Walport, Mark J. (2001).
10.1111/j.1467-7652.2010.00552.x. [1] "Complement. First of two parts". N Engl J Med. 344
(14): 1058–66. doi:10.1056/NEJM200104053441406.
Further reading PMID 11287977.
• Walport MJ; Rosen, Fred S.; Walport, Mark J. (2001).
• Bradley, D T; Zipfel, P F; Hughes, A E (2011). "Complement. Second of two parts". N Engl J Med. 344
"Complement in age-related macular degeneration: a (15): 1140–4. doi:10.1056/NEJM200104123441506.
focus on function". Eye 25 (6): 683–93. doi:10.1038/ PMID 11297706.
eye.2011.37. PMC 3178140. PMID 21394116.
http://www.pubmedcentral.nih.gov/
articlerender.fcgi?tool=pmcentrez&artid=3178140.
External links
• Kardys, I. et al. (2006). "A common polymorphism in • GeneReviews/NCBI/NIH/UW entry on Atypical
the complement factor h gene is associated with Hemolytic-Uremic Syndrome
increased risk of myocardial infarction the • GeneReviews/NCBI/NIH/UW entry on Dense Deposit
rotterdam study". J. Am. Coll. Cardiol. 47 (8): 1568–75. Disease/Membranoproliferative Glomerulonephritis
doi:10.1016/j.jacc.2005.11.076. PMID 16630992. Type II
• Pío R, Elsasser TH, Martínez A, Cuttitta F (2002). • OMIM entries on Atypical Hemolytic-Uremic
"Identification, characterization, and physiological Syndrome
actions of factor H as an adrenomedullin binding • MeSH Complement+Factor+H
protein present in human plasma". Microsc. Res. Tech.
57 (1): 23–7. doi:10.1002/jemt.10047. PMID 11921353.
Retrieved from "http://en.wikipedia.org/w/index.php?title=Factor_H&oldid=462605902"
Categories:
• Human proteins
• Complement system
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