Ficolin M (Ficolin 1)

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The ficolins are a group of soluble animal proteins with roles in innate immunity[1][2][3][4][5]. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)[2][6]. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands[4]. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening[7]. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied[5][6][7][8][9][10][11][12]. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications[13]. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs[11].

See also: paradigm page for Ficolins/Mannose-binding protein


CFG Participating Investigators contributing to the understanding of this paradigm

Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

Progress toward understanding this GBP paradigm

This section documents what is currently known about Ficolin M, its carbohydrate ligand(s), and how they interact to mediate cell communication.

Carbohydrate ligands

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides[7].

Cellular expression of GBP and ligands

M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells[2][6][8]. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml[12][14].

Biosynthesis of ligands

Pathways for ganglioside biosynthesis have been described (GT Database).
O-acetylation at positions C-7,8,9 of sialic acid is catalyzed by O-acetyltransferase enzymes associated with the Golgi membrane in mammals[15][16]. Sialic acid O-acetyltransferases have also been identified in bacteria, but they are not homologous to the vertebrate enzymes[17].


The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography[9][10]. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A [18]. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis[7].

Biological roles of GBP-ligand interaction

Soluble M-ficolin has been shown to bind to Staphylococcus aureus through GlcNAc[8]. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface[19].

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for ficolin.

Glycan profiling

Glycan profiling has not been performed.

Glycogene microarray

No data available.

Knockout mouse lines

Glycan array

The soluble ficolins have been extensively examined using the CFG glycan array (28 screens).
Human M-ficolin investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click here, here, here, here, here, here, and here), and of 4 variants with the following point mutations in the recognition domain: G221F (click here, here, and here), A256V (click here, here, and here), G221F/A256V (click here) and Y271F (click here and here). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click here and here).

Related GBPs

This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in D. melanogaster and C. elegans. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L (CFG data) and H (CFG data) are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently[20]. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin[21].


  1. Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)
  2. 2.0 2.1 2.2 Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)
  3. Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)
  4. 4.0 4.1 Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006)
  5. 5.0 5.1 Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)
  6. 6.0 6.1 6.2 Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)
  7. 7.0 7.1 7.2 7.3 Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009)
  8. 8.0 8.1 8.2 Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)
  9. 9.0 9.1 Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)
  10. 10.0 10.1 Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)
  11. 11.0 11.1 Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)
  12. 12.0 12.1 Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)
  13. Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)
  14. Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)
  15. Higa, H.H., Manzi, A. and Varki, A. O-acetylation and de-O-acetylation of sialic acids. Purification, characterization, and properties of a glycosylated rat liver esterase specific for 9-O-acetylated sialic acids. J Biol Chem 264, 19435-19442 (1989)
  16. Butor, C., Higa, H.H. and Varki, A. Structural, immunological, and biosynthetic studies of a sialic acid-specific O-acetylesterase from rat liver. J Biol Chem 268, 10207-10213 (1993)
  17. Lewis, A.L., Hensler, M.E., Varki, A. and Nizet, V. The group B streptococcal sialic acid O-acetyltransferase is encoded by neuD, a conserved component of bacterial sialic acid biosynthetic gene clusters. J Biol Chem 281, 11186-11192 (2006)
  18. Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)
  19. Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, and Garred P. Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)
  20. Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, and Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)
  21. Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palaniyar N, Wallis R, Mollenhauer J, and Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)


The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

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