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Properdin

From Wikipedia, the free encyclopedia

CFP
Identifiers
AliasesCFP, BFD, PFC, PFD, PROPERDIN, complement factor properdin, properdin
External IDsOMIM: 300383; MGI: 97545; GeneCards: CFP
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

5199

18636

Ensembl

ENSG00000126759

ENSMUSG00000001128

UniProt

P27918

P11680

RefSeq (mRNA)

NM_002621
NM_001145252

NM_008823

RefSeq (protein)

NP_001138724
NP_002612

NP_032849

Location (UCSC)Chr X: 47.62 – 47.63 MbChr X: 20.79 – 20.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Properdin is a protein that in humans is encoded by the CFP (complement factor properdin) gene. Properdin and factor H are regulatory proteins in the alternative complement pathway. Properdin is an up-regulator, stabilizing the C3bBb complex, and factor H is the down-regulator, promoting proteolytic degradation of C3b. Factor H is primarily produced in the liver, whereas properdin is sourced in neutrophils, monocytes, T cells and bone marrow progenitor cell line.[5][6][7]

Properdin is plasma glycoprotein that activates the complement system of the innate immune system. It is found in plasma and primarily produced by leukocytes. This protein binds to bacterial cell walls and dying human cells to stabilize the C3 and C5-convertase enzyme complexes to form an attack complex that leads to the lysis of the cell. The complement system is made of plasma and membrane-bound proteins that go through the blood to get rid of pathogens and damaged cells. Activation of the complement system occurs via three pathways, the classical, lectin, and alternative pathways. Activation of the alternative pathway occurs in bacteria, yeast, and parasites and is stimulated by antibody-antigen complexes made of IgG or IgA. Properdin and factor H are important regulatory proteins of the alternative pathway, which is initiated by a conformational change in C3 cleaved at a single site by the serine protease C3 convertase.[8]

Structure

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Properdin is a gamma globulin protein composed of multiple identical protein subunits with a separate ligand-binding site. Native properdin occurs in head-to-tail dimers, trimers and tetramers in the fixed ratio 22:52:28.[9] Under physiological conditions, properdin forms P2, P3, and P4 in a 26:54:20 ratio by a head-to-tail formation of monomers.[10] The structure is a single-chain molecule made of 469 amino acids, with the leader sequence consisting of 27-amino acids. Every properdin monomer is made of six thrombospondin type 1 repeat (TSR) domains labeled TSR1-6, each including a core of three antiparallel strands with three disulfides, totaling 60 amino acids.[11] Properdin undergoes post-translation through C-mannosylation, O-fucosylation, N-glycosylation, and C-glycosylation.[12][13]

Function

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It is known that it participates in some specific immune responses. It plays a part in tissue inflammation as well as the engulfing of pathogens by phagocytes. In addition it is known to help to neutralize some viruses.

The properdin promotes the association of C3b with Factor B and provides a focal point for the assembly of C3bBb on a surface. It binds to preformed alternative pathway C3-convertases.[14] Properdin also inhibits the Factor H – mediated cleavage of C3b by Factor I. Properdin, in addition to Factor H, can bind to glycosaminoglycan (GAG) epitopes by renal tubular heparin sulfates.[15] Additionally, the binding of properdin to Salmonella typhosa lipopolysaccharide (LPS) and Neisseria meningitidis lipopolysaccharide result in activation of the complementary alternative pathway.[16] Furthermore, it binds to various microbial surfaces, resulting in the assembly of the alternative pathway C3 convertase.[17]

Alternative pathway. Properdin is the "P" in the blue circles. (Some labels are in Polish.)

Properdin promotes phagocytosis of apoptotic T cells in two ways. One way is through binding to apoptotic T cells, which initiates AP-mediated C3b deposition, promoting cell uptake through CR3-bearing phagocytes. Another way is through properdin binding on T cells and directly mediating phagocytes. Properdin contains abilities to eliminate apoptotic cells in order to reduce harmful inflammatory and autoimmune reactions. Additionally, properdin binds malignant T cell lines, therefore, properdin deficiency may be a risk in the development of specific T cell malignancies.[18]

The alternative pathway is not dependent on antibodies. This branch of the complement system is activated by IgA immune complexes and bacterial endotoxins, polysaccharides, and cell walls, and results in producing anaphylatoxins, opsonins, chemotactic factors, and the membrane attack complex, all of which help fight pathogens.

Complement pathway

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The complement pathway may be initiated by three pathways, including the classical, lectin, and alternative pathways.

  • In the classical pathway, C1 complex recognizes two IgGs or one pentamer IgM, forming an antigen-antibody complex.
  • For the lectin pathway, mannose-binding lectin (MBL) and their associated serine proteins (MASPs), recognize carbohydrates on pathogens, which initiates the C3 convertase C4b2b.
  • The alternative pathway is different due to its spontaneous activation in fluid phase by hydrolysis of C3 to C3(H2O). C3(H2O) can bind to Factor B, which can then be cleaved by the serum protease Factor D, resulting in formation of C3(H2O)Bb. C3(H2O)Bb can cleave additional C3 molecules, creating C3b and C3a.

Tissue distribution

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Cell Source Form Stimulus
Primary Cells
Monocytes mRNA; Protein Constitutive
Dendritic cells mRNA; Protein Constitutive
Primary T cells mRNA Constitutive
Mast cells Protein Constitutive
Granulocytes mRNA; Protein Constitutive
Macrophages mRNA Constitutive
Adipocytes mRNA; Protein Constitutive
Endothelial cells mRNA; Protein Shear stress

Sources: Monocytes;[19] Dendritic cells;[20] Primary T cells;[21] Mast cells;[22] Granulocytes;[23] Macrophages;[24] Adipocytes;[25] Endothelial cells [26]

Most complement systems are synthesized by hepatocytes in the liver, however, properdin is synthesized by neutrophils, monocytes, and T cells. Properdin is a positive regulator of the alternative pathway through its mechanism of stabilizing the C3 convertase (C3bBb). Primary T cells, monocytes, macrophages, dendritic cells, granulocytes, and mast cells synthesize mRNA to secrete properdin. Functional properdin is a product of human liver-derived HEP G2 cells. Properdin localized in the granules of neutrophils are released by TNF, TNF/fMLP, PMA, C5a, or IL-8.[5] Additionally, neutrophils promote complement activation upon binding of cytokines, which stabilizes the alternative pathway via release of properdin, increasing defense against microorganisms. Properdin sourced from T cells promote phagocytosis of apoptotic T cells, which is an indication of their function in recognizing and clearing out apoptotic cells.[6] Properdin is also sourced in endothelial cells along with the other complement proteins. Endothelial gene transcripts are induced when shear stress occurs, followed by properdin release into extracellular compartments.[27]

Properdin plays an important role in tissue regulation, energy metabolism, and lipid metabolism. An experiment in properdin deficient mice concluded that properdin deficiency results in fat storage and less energy output in comparison to wild-type mice. Properdin regulates fatty acid uptake into adipose tissue.[28] Complement proteins are also involved in cartilage transformation. C3, factor B and properdin have been observed in the resting zone of cartilage, and the alternative pathway likely plays a role in cartilage development.[29]

Deficiency

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Complement defects are associated with an increased risk of infectious or local and inflammatory thrombotic disorders. These complement-linked disorders are rare but tend to show up during childhood. Hereditary angioedema (HAE) result from impaired function of the C1 inhibitor, and complement disorders result in renal disorders, including atypical hemolytic uremic syndrome (aHUS) or C3 glomerulopathy (C3G).[30]

Properdin deficiency is a rare X-linked disease in which properdin is deficient. Affected individuals are susceptible to fulminant meningococcal disease,[31] whereas defects of the classical pathway increase the risk of autoimmune disorders. Properdin deficiency has been reported in more than 70 patients, and is linked to infections with Neisseria meningitides and Neisseria gonorrhoea. Mortality rates are higher in individuals with properdin deficiency in comparison to those with terminal complement deficiencies. Three classes of properdin deficiencies are

  • Type I: Properdin levels are unable to be detected
  • Type II: Properdin levels are from 1-10% in comparison to normal levels; function is intact
  • Type III: Properdin levels are normal but the function is absent[32]

Evaluations for properdin deficiency may take place in patients with frequenct Neisserial infections with a functioning classical complement pathway (CH50). The AH50 assay is based on the lysis of unsensitized rabbit erythrocytes, however, normal results have been reported in patients with Type I properdin deficiency. Family history of X-linked inheritance should be considered. Further testing includes: Factor D Function by Hemolytic Assay, Properdin Level by ELISA, and gene sequencing to detect mutations for confirmation.[33]

Patients with Factor D deficiency or properdin deficiency are advised to receive meningococcal vaccinations and frequent evaluations for meningococcal antibodies. For those with recurring infections, prophylactic antibiotics are administered.

History

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Properdin was discovered in 1954 by Dr. Louis Pillemer of the Institute of Pathology (now the Department of Pathology at Case Western Reserve University). He was an American immunologist and investigated the complement system, a system of defense not dependent upon antibodies. At Case Western, he was the first to purify tetanus and dipheria toxins, which were used to develop the DPT vaccine.[34]

The complement system was discovered more than 100 years ago, when experiments proved that lysing of microbial targets could be induced by a "complementary" mixture of human serum and antibody mixtures.[35] The alternative pathway was discovered when Dr. Louis Pillemer observed partial purification of the plasma protein properdin, and its ability to activate the complement system on various targets without using antibodies.[36] In the 1970's, evidence was found of an antibody-independent complement activation pathway. Protein purification methods were utilized to model complement activation, such as the alternative pathway C3 convertase.[37]

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000126759 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001128 – 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. 1 2 Camous L, Roumenina L, Bigot S, Brachemi S, Frémeaux-Bacchi V, Lesavre P, et al. (January 2011). "Complement alternative pathway acts as a positive feedback amplification of neutrophil activation". Blood. 117 (4): 1340–1349. doi:10.1182/blood-2010-05-283564. PMID 21063021.
  6. 1 2 Kemper C, Mitchell LM, Zhang L, Hourcade DE (July 2008). "The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis". Proceedings of the National Academy of Sciences of the United States of America. 105 (26): 9023–9028. Bibcode:2008PNAS..105.9023K. doi:10.1073/pnas.0801015105. PMC 2449358. PMID 18579773.
  7. ↑ 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): 501–516. doi:10.1084/jem.151.3.501. PMC 2185797. PMID 6444659.
  8. ↑ Carroll MV, Sim RB (September 2011). "Complement in health and disease". Advanced Drug Delivery Reviews. Complement Monotoring of Nanomedicines and Implants. 63 (12): 965–975. doi:10.1016/j.addr.2011.06.005. PMID 21704094.
  9. ↑ Smith C, Pangburn M, Vogel CW, Müller-Eberhard H (1984). "Molecular Architecture of Human Properdin, a Positive Regulator of the Alternative Pathway of Complement". The Journal of Biological Chemistry. 259 (7): R4582–4588. doi:10.1016/S0021-9258(17)43086-9. PMID 6707020.
  10. ↑ Pangburn MK (January 1989). "Analysis of the natural polymeric forms of human properdin and their functions in complement activation". Journal of Immunology. 142 (1). Baltimore: 202–207. doi:10.4049/jimmunol.142.1.202. PMID 2909614.
  11. ↑ Goundis D, Reid KB (September 1988). "Properdin, the terminal complement components, thrombospondin and the circumsporozoite protein of malaria parasites contain similar sequence motifs". Nature. 335 (6185): 82–85. Bibcode:1988Natur.335...82G. doi:10.1038/335082a0. PMID 3045564.
  12. ↑ Hartmann S, Hofsteenge J (September 2000). "Properdin, the positive regulator of complement, is highly C-mannosylated". The Journal of Biological Chemistry. 275 (37): 28569–28574. doi:10.1074/jbc.m001732200. PMID 10878002.
  13. ↑ Yang Y, Liu F, Franc V, Halim LA, Schellekens H, Heck AJ (November 2016). "Hybrid mass spectrometry approaches in glycoprotein analysis and their usage in scoring biosimilarity". Nature Communications. 7 (1) 13397. Bibcode:2016NatCo...713397Y. doi:10.1038/ncomms13397. PMC 5105167. PMID 27824045.
  14. ↑ Hourcade DE (January 2006). "The role of properdin in the assembly of the alternative pathway C3 convertases of complement". The Journal of Biological Chemistry. 281 (4): 2128–2132. doi:10.1074/jbc.m508928200. PMID 16301317.
  15. ↑ Zaferani A, Vivès RR, van der Pol P, Navis GJ, Daha MR, van Kooten C, et al. (September 2012). "Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate". The Journal of Biological Chemistry. 287 (37): 31471–31481. doi:10.1074/jbc.M112.380386. PMC 3438980. PMID 22815489.
  16. ↑ Kimura Y, Miwa T, Zhou L, Song WC (January 2008). "Activator-specific requirement of properdin in the initiation and amplification of the alternative pathway complement". Blood. 111 (2): 732–740. doi:10.1182/blood-2007-05-089821. PMC 2200840. PMID 17916747.
  17. ↑ Spitzer D, Mitchell LM, Atkinson JP, Hourcade DE (August 2007). "Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly". Journal of Immunology. 179 (4). Baltimore: 2600–2608. doi:10.4049/jimmunol.179.4.2600. PMID 17675523.
  18. ↑ Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. (October 2006). "The consensus coding sequences of human breast and colorectal cancers". Science. 314 (5797). New York, N.Y.: 268–274. Bibcode:2006Sci...314..268S. doi:10.1126/science.1133427. PMID 16959974.
  19. ↑ Uchiyama S, Keller N, Schlaepfer E, Grube C, Schuepbach RA, Speck RF, et al. (July 2016). "Interferon α-Enhanced Clearance of Group A Streptococcus Despite Neutropenia". The Journal of Infectious Diseases. 214 (2): 321–328. doi:10.1093/infdis/jiw157. PMID 27338768.
  20. ↑ Dixon KO, O'Flynn J, Klar-Mohamad N, Daha MR, van Kooten C (March 2017). "Properdin and factor H production by human dendritic cells modulates their T-cell stimulatory capacity and is regulated by IFN-γ". European Journal of Immunology. 47 (3): 470–480. doi:10.1002/eji.201646703. PMC 5363362. PMID 28105653.
  21. ↑ Schwaeble W, Dippold WG, Schäfer MK, Pohla H, Jonas D, Luttig B, et al. (September 1993). "Properdin, a positive regulator of complement activation, is expressed in human T cell lines and peripheral blood T cells". Journal of Immunology. 151 (5). Baltimore: 2521–2528. doi:10.4049/jimmunol.151.5.2521. PMID 8360474.
  22. ↑ Stover CM, Luckett JC, Echtenacher B, Dupont A, Figgitt SE, Brown J, et al. (March 2008). "Properdin plays a protective role in polymicrobial septic peritonitis". Journal of Immunology. 180 (5). Baltimore: 3313–3318. doi:10.4049/jimmunol.180.5.3313. PMID 18292556.
  23. ↑ Wirthmueller U, Dewald B, Thelen M, Schäfer MK, Stover C, Whaley K, et al. (May 1997). "Properdin, a positive regulator of complement activation, is released from secondary granules of stimulated peripheral blood neutrophils". Journal of Immunology. 158 (9). Baltimore: 4444–4451. doi:10.4049/jimmunol.158.9.4444. PMID 9127010.
  24. ↑ Reis ES, Barbuto JA, Isaac L (May 2006). "Human monocyte-derived dendritic cells are a source of several complement proteins". Inflammation Research. 55 (5): 179–184. doi:10.1007/s00011-006-0068-y. PMID 16830104.
  25. ↑ Pattrick M, Luckett J, Yue L, Stover C (February 2009). "Dual role of complement in adipose tissue". Molecular Immunology. 46 (5): 755–760. doi:10.1016/j.molimm.2008.09.013. PMID 18954909.
  26. ↑ Jeon H, Yoo SM, Choi HS, Mun JY, Kang HG, Lee J, et al. (November 2017). "Extracellular vesicles from KSHV-infected endothelial cells activate the complement system". Oncotarget. 8 (59): 99841–99860. doi:10.18632/oncotarget.21668. PMC 5725135. PMID 29245944.
  27. ↑ Bongrazio M, Pries AR, Zakrzewicz A (January 2003). "The endothelium as physiological source of properdin: role of wall shear stress". Molecular Immunology. 39 (11): 669–675. doi:10.1016/S0161-5890(02)00215-8. PMID 12493642.
  28. ↑ Gauvreau D, Roy C, Tom FQ, Lu H, Miegueu P, Richard D, et al. (May 2012). "A new effector of lipid metabolism: complement factor properdin". Molecular Immunology. 7th International EMBO Workshop on Antigen Presentation and Processing. 51 (1): 73–81. doi:10.1016/j.molimm.2012.02.110. PMID 22387270.
  29. ↑ Andrades JA, Nimni ME, Becerra J, Eisenstein R, Davis M, Sorgente N (September 1996). "Complement proteins are present in developing endochondral bone and may mediate cartilage cell death and vascularization". Experimental Cell Research. 227 (2): 208–213. doi:10.1006/excr.1996.0269. PMID 8831558.
  30. ↑ Mayatepek E, Grauer M, HäNsch GM, Sonntag HG (October 1993). "Deafness, complement deficiencies and immunoglobulin status in patients with meningococcal diseases due to uncommon serogroups". The Pediatric Infectious Disease Journal. 12 (10): 808–811. doi:10.1097/00006454-199310000-00002. PMID 8284115.
  31. ↑ Dr. Lars Otto Uttenthal Properdin September 01 2005 Archived 2012-04-02 at the Wayback Machine
  32. ↑ SjÖHolm AG (October 1990). "Inherited complement deficiency states: implications for immunity and immunological disease". Apmis. 98 (10): 861–874. doi:10.1111/j.1699-0463.1990.tb05008.x. PMID 2147105.
  33. ↑ Fijen CA, van den Bogaard R, Schipper M, Mannens M, Schlesinger M, Nordin FG, et al. (1999). "Properdin deficiency: molecular basis and disease association". Molecular Immunology. 36 (13–14): 863–867. doi:10.1016/S0161-5890(99)00107-8. PMID 10698340.
  34. ↑ Kuby Immunology (8th ed.). W. H. Freeman and Company. 2019. pp. 377–380. ISBN 978-1-319-26722-3.
  35. ↑ Whaley K (1985). An introduction to the complement system. In: Whaley, K. (Ed.), Methods in Complement for Clinical Immunologists. Churchhill Livingstone, Edinburgh. pp. 1–20.
  36. ↑ Pillemer L. The properdin system and immunity. Demonstration and isolation of a new serum protein, properdin, and its role in immune phenomena. Science 120. pp. 279–285.
  37. ↑ Pangburn MK, Müller-Eberhard HJ (1984). "The alternative pathway of complement". Springer Seminars in Immunopathology. 7 (2–3): 163–192. doi:10.1007/BF01893019. PMID 6238433.
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