Complement factor I

Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene. Complement factor I (factor I) is a protein of the complement system, first isolated in 1966 in guinea pig serum,[5] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.[6] It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.[7]

CFI
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCFI, AHUS3, ARMD13, C3BINA, C3b-INA, FI, IF, KAF, complement factor I
External IDsOMIM: 217030 MGI: 105937 HomoloGene: 171 GeneCards: CFI
Orthologs
SpeciesHumanMouse
Entrez

3426

12630

Ensembl

ENSG00000205403

ENSMUSG00000058952

UniProt

P05156
Q8WW88

Q61129

RefSeq (mRNA)

NM_000204
NM_001318057
NM_001331035

NM_007686
NM_001329552

RefSeq (protein)

NP_001316481
NP_031712

Location (UCSC)Chr 4: 109.74 – 109.8 MbChr 3: 129.63 – 129.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Synthesis

The gene for Factor I in humans is located on chromosome 4.[8] Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, keratinocytes, and endothelial cells.[9][10][11] When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions.[12] Then, factor I is cleaved by furin to yield the mature factor I protein, which is a disulfide-linked dimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton).[13] Only the mature protein is active.

Structure

Factor I is a glycoprotein heterodimer consisting of a disulfide linked heavy chain and light chain.[14]

The factor I heavy chain has four domains: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) domains.[15] the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by the substrate (either C3b or C4b) and a cofactor protein (Factor H, C4b-binding protein, complement receptor 1, and membrane cofactor protein).[16] Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery.[16] The LDL-receptor domains contain one Calcium-binding site each.

The factor I light chain contains only the serine protease domain. This domain contains the catalytic triad His-362, Asp-411, and Ser-507, which is responsible for specific cleavage of C3b and C4b.[15] Conventional protease inhibitors do not completely inactivate Factor I[17] but they can do so if the enzyme is pre-incubated with its substrate: this supports the proposed rearrangement of the molecule upon binding to the substrate.

Both heavy and light chains bear Asn-linked glycans, on three distinct glycosylation sites each.

Crystal structure the crystal structure of human Factor I has been deposited as PDB: 2XRC.

Clinical significance

Dysregulated factor I activity has clinical implications. Loss of function mutations in the Complement Factor I gene lead to low levels of factor I which results in increased complement activity. Factor I deficiency in turn leads to low levels of complement component 3 (C3), factor B, factor H and properdin in blood, due to unregulated activation of C3 convertase, and to low levels of IgG, due to loss of iC3b and C3dg production. In addition to the following diseases, low factor I is associated with recurrent bacterial infections in children.

Research suggests that mutations in the CFI gene contribute to development of age-related macular degeneration.[18] This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.[19]

Atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome is caused by complement overactivation.[20] Heterozygous mutations in the serine protease domain of the CFI gene account for 5-10% of cases.[20]

References
  1. GRCh38: Ensembl release 89: ENSG00000205403 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000058952 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Nelson RA, Jensen J, Gigli I, Tamura N (March 1966). "Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum". Immunochemistry. 3 (2): 111–35. doi:10.1016/0019-2791(66)90292-8. PMID 5960883.
  6. Lachmann PJ, Müller-Eberhard HJ (April 1968). "The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement". Journal of Immunology. 100 (4): 691–8. PMID 5645214.
  7. Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM (August 2011). "Complement factor I in health and disease". Molecular Immunology (Submitted manuscript). 48 (14): 1611–20. doi:10.1016/j.molimm.2011.04.004. PMID 21529951. S2CID 37521895.
  8. Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ (July 1987). "Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4". The Journal of Biological Chemistry. 262 (21): 10065–71. doi:10.1016/S0021-9258(18)61076-2. PMID 2956252.
  9. Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, Walport MJ (February 1996). "The molecular basis of hereditary complement factor I deficiency". The Journal of Clinical Investigation. 97 (4): 925–33. doi:10.1172/JCI118515. PMC 507137. PMID 8613545.
  10. Julen N, Dauchel H, Lemercier C, Sim RB, Fontaine M, Ripoche J (January 1992). "In vitro biosynthesis of complement factor I by human endothelial cells". European Journal of Immunology. 22 (1): 213–7. doi:10.1002/eji.1830220131. PMID 1530917. S2CID 30130789.
  11. Whaley K (March 1980). "Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes". The Journal of Experimental Medicine. 151 (3): 501–16. doi:10.1084/jem.151.3.501. PMC 2185797. PMID 6444659.
  12. Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, Dwek RA, Rudd PM, Sim RB (November 2006). "Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1764 (11): 1757–66. CiteSeerX 10.1.1.712.1764. doi:10.1016/j.bbapap.2006.09.007. PMID 17055788.
  13. "FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-30.
  14. "CFI complement factor I [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-27.
  15. Sanchez-Gallego JI, Groeneveld TW, Krentz S, Nilsson SC, Villoutreix BO, Blom AM (April 2012). "Analysis of binding sites on complement factor I using artificial N-linked glycosylation". The Journal of Biological Chemistry. 287 (17): 13572–83. doi:10.1074/jbc.M111.326298. PMC 3340171. PMID 22393059.
  16. Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM (August 2011). "Structural basis for complement factor I control and its disease-associated sequence polymorphisms". Proceedings of the National Academy of Sciences of the United States of America. 108 (31): 12839–44. Bibcode:2011PNAS..10812839R. doi:10.1073/pnas.1102167108. PMC 3150940. PMID 21768352.
  17. Ekdahl KN, Nilsson UR, Nilsson B (June 1990). "Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I". Journal of Immunology. 144 (11): 4269–74. PMID 2140392.
  18. Wang Q, Zhao HS, Li L (2016-02-18). "Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration: a Meta-analysis of literature". International Journal of Ophthalmology. 9 (2): 298–305. doi:10.18240/ijo.2016.02.23. PMC 4761747. PMID 26949655.
  19. Tan PL, Garrett ME, Willer JR, Campochiaro PA, Campochiaro B, Zack DJ, Ashley-Koch AE, Katsanis N (March 2017). "Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration". Investigative Ophthalmology & Visual Science. 58 (3): 1570–1576. doi:10.1167/iovs.16-20867. PMC 6022411. PMID 28282489.
  20. Kavanagh D, Goodship TH, Richards A (November 2013). "Atypical hemolytic uremic syndrome". Seminars in Nephrology. 33 (6): 508–30. doi:10.1016/j.semnephrol.2013.08.003. PMC 3863953. PMID 24161037.

Further reading
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