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Table of Contents
Vol. 2, No. 1, 2010
Issue release date: December 2009
Free Access
J Innate Immun 2010;2:17–23
(DOI:10.1159/000233475)

Structural Insights into the Recognition Properties of Human Ficolins

Garlatti V. · Martin L. · Lacroix M. · Gout E. · Arlaud G.J. · Thielens N.M. · Gaboriaud C.
Institut de Biologie Structurale JP Ebel, Grenoble, France
email Corresponding Author

Abstract

Innate immunity relies upon the ability of a variety of recognition molecules to sense pathogens through conserved molecular signatures that are often carbohydrates. Ficolins are oligomeric proteins assembled from collagen-like stalks and fibrinogen-like domains that have the ability to sense these molecular patterns on both pathogens and apoptotic cell surfaces. Three ficolins, termed L, H and M, have been identified in humans. They differ in their localization and concentration in extracellular fluids, their mode of secretion and their recognition properties. From a structural point of view, ficolins are assembled from basal trimeric subunits comprising a collagen-like triple helix and a globular domain composed of 3 fibrinogen-like domains. The globular domains are responsible for sensing danger signals whereas the collagen-like stalks provide a link with immune effectors. This review mainly focuses on the structure and recognition properties of the 3 human ficolins, as revealed by recent crystallographic analysis of their recognition domains. The ligand binding sites have been identified in the 3 ficolins and their recognition mechanisms have been characterized at the atomic level. In the case of M-ficolin, a structural transition at acidic pH disables the binding pocket, and thus likely participates in the functional cycle of this protein.


 goto top of outline Key Words

  • Complement
  • Carbohydrate specificity
  • Ficolins
  • Innate immunity
  • Pattern Recognition Receptor
  • X-ray structures

 goto top of outline Abstract

Innate immunity relies upon the ability of a variety of recognition molecules to sense pathogens through conserved molecular signatures that are often carbohydrates. Ficolins are oligomeric proteins assembled from collagen-like stalks and fibrinogen-like domains that have the ability to sense these molecular patterns on both pathogens and apoptotic cell surfaces. Three ficolins, termed L, H and M, have been identified in humans. They differ in their localization and concentration in extracellular fluids, their mode of secretion and their recognition properties. From a structural point of view, ficolins are assembled from basal trimeric subunits comprising a collagen-like triple helix and a globular domain composed of 3 fibrinogen-like domains. The globular domains are responsible for sensing danger signals whereas the collagen-like stalks provide a link with immune effectors. This review mainly focuses on the structure and recognition properties of the 3 human ficolins, as revealed by recent crystallographic analysis of their recognition domains. The ligand binding sites have been identified in the 3 ficolins and their recognition mechanisms have been characterized at the atomic level. In the case of M-ficolin, a structural transition at acidic pH disables the binding pocket, and thus likely participates in the functional cycle of this protein.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Medzhitov R: Recognition of microorganisms and activation of the immune response. Nature 2007;449:819–826.
  2. Fujita T, Matsushita M, Endo Y: The lectin-complement pathway: its role in innate immunity and evolution. Immunol Rev 2004;198:185–202.
  3. Matsushita M, Endo Y, Taira S, Sato Y, Fujita T, Ichikawa N, Nakata M, Mizuochi T: A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin. J Biol Chem 1996;271:2448–2454.
  4. Sugimoto R, Yae Y, Akaiwa M, Kitajima S, Shibata Y, Sato H, Hirata J, Okochi K, Izuhara K, Hamasaki N: Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J Biol Chem 1998;273:20721–20727.
  5. Harumiya S, Takeda K, Sugiura T, Fukumoto Y, Tachikawa H, Miyazono K, Fujimoto D, Ichijo H: Characterization of ficolins as novel elastin-binding proteins and molecular cloning of human ficolin-1. J Biochem (Tokyo) 1996;120:745–751.
  6. Honoré C, Rørvig S, Munthe-Fog L, Hummelshøj T, Madsen HO, Borregaard N, Garred P: The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 2008;45:2782–2789.
  7. Krarup A, Thiel S, Hansen A, Fujita T, Jensenius JC: L-ficolin is a pattern recognition molecule specific for acetyl groups. J Biol Chem 2004;279:47513–47519.
  8. Lynch NJ, Roscher S, Hartung T, Morath S, Matsushita M, Maennel DN, Kuraya M, Fujita T, Schwaeble WJ: L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J Immunol 2004;172:1198–1202.
  9. Ma YG, Cho MY, Zhao M, Park JW, Matsushita M, Fujita T, Lee BL: Human mannose-binding lectin and L-ficolin function as specific pattern recognition proteins in the lectin activation pathway of complement. J Biol Chem 2004;279:25307–25312.
  10. Aoyagi Y, Adderson EE, Min JG, Matsushita M, Fujita T, Takahashi S, Okuwaki Y, Bohnsack JF: Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B Streptococci. J Immunol 2005;174:418–425.
  11. Tsujimura M, Ishida C, Sagara Y, Miyazaki T, Murakami K, Shiraki H, Okochi K, Maeda Y: Detection of serum thermolabile beta-2 macroglycoprotein (Hakata antigen) by enzyme-linked immunosorbent assay using polysaccharide produced by Aerococcus viridans. Clin Diagn Lab Immunol 2001;8:454–459.
  12. Lacroix M, Dumestre-Pérard C, Schoehn G, Houen G, Cesbron J-Y, Arlaud GJ, Thielens NM: Residue Lys57 in the collagenous region of human L-ficolin and its counterpart Lys47 in H-ficolin play a key role in the interaction with the MASPs and the collectin receptor calreticulin. J Immunol 2009;182:456–465.
  13. Liu Y, Endo Y, Iwaki D, Nakata M, Matsushita M, Wada I, Inoue K, Munakata M, Fujita T: Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 2005;175:3150–3156.
  14. Frederiksen PD, Thiel S, Larsen CB, Jensenius JC: M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 2005;62:462–473.
  15. Teh C, Le Y, Lee SH, 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 2000;101:225–232.
  16. Matsushita M, Fujita T: Ficolins and the lectin complement pathway. Immunol Rev 2001;180:78–85.
  17. Thiel S, Vorup-Jensen T, Stover CM, Schwaeble W, Laursen SB, Poulsen K, Willis AC, Eggleton P, Hansen S, Holmskov U, Reid KB, Jensenius JC: A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997;386:506–510.
  18. Pagh R, Duus K, Laursen I, Hansen PR, Thielens N, Arlaud GJ, Kongerslev L, Højrup P, Houen G: The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with MBL through the binding site for MBL-associated serine proteases. FEBS J 2008;275:515–526.
  19. Matsushita M, Fujita T: Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med 1992;176:1497–1502.
  20. Dahl MR, Thiel S, Matsushita M, Fujita T, Willis AC, Christensen T, Vorup-Jensen T, Jensenius JC: MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 2001;15:127–135.
  21. Stover CM, Thiel S, Thelen M, Lynch NJ, Vorup-Jensen T, Jensenius JC, Schwaeble W: Two constituents of the initiation complex of the mannan-binding lectin activation pathway of complement are encoded by a single structural gene. J Immunol 1999;162:3481–3490.
  22. Takahashi M, Endo Y, Fujita T, Matsushita M: A truncated form of mannose-binding lectin-associated serine protease (MASP)-2 expressed by alternative polyadenylation is a component of the lectin complement pathway. Int Immunol 1999;11:859–863.
  23. Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C: Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 2007;26:623–633.
  24. Garlatti V, Martin L, Gout E, Reiser JB, Fujita T, Arlaud GJ, Thielens NM, Gaboriaud C: Structural sensing by M-ficolins and its control by a pH-dependent conformational switch. J Biol Chem 2007;282:35814–35820.
  25. Tanio M, Kondo S, Sugio S, Kohno T: Trivalent recognition unit of innate immunity system: crystal structure of trimeric human M-ficolin fibrinogen-like domain. J Biol Chem 2007;282:3889–3895.
  26. Kairies N, Beisel HG, Fuentes-Prior P, Tsuda R, Muta T, Iwanaga S, Bode W, Huber R, Kawabata SI: The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems. Proc Natl Acad Sci USA 2001;98:13519–13524.
  27. Gaboriaud C, Juanhuix J, Gruez A, Lacroix M, Darnault C, Pignol D, Verger D, Fontecilla-Camps JC, Arlaud GJ: The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 2003;278:46974–46982.
  28. Sheriff S, Chang CY, Ezekowitz AB: Human mannose-binding protein carbohydrate recognition domain trimerizes through a triple a-helical coiled-coil. Nat Struct Biol 1994;1:789–794.
  29. Tanio M, Kohno T: Histidine-regulated activity of M-ficolin. Biochem J 2009;417:485–491.
  30. Kählig H, Kolarich D, Zayni S, Scheberl A, Kosma P, Schaffer C, Messner P: N-acetylmuramic acid as capping element of alpha-D-fucose-containing S-layer glycoprotein glycans from Geobacillus tepidamans GS5-97T. J Biol Chem2005;280:20292–20299.
  31. Bilyy R, Stoika R: Search for novel cell surface markers of apoptotic cells. Autoimmunity 2007;40:249–253.

 goto top of outline Author Contacts

Dr. Christine Gaboriaud
Institut de Biologie Structurale JP Ebel
41 rue Jules Horowitz
FR–38041 Grenoble Cedex 1 (France)
Tel. +33 4 3878 9599, Fax +33 4 3878 5122, E-Mail christine.gaboriaud@ibs.fr


 goto top of outline Article Information

Received: February 25, 2009
Accepted after revision: May 26, 2009
Published online: August 6, 2009
Number of Print Pages : 7
Number of Figures : 3, Number of Tables : 0, Number of References : 31


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 2, No. 1, Year 2010 (Cover Date: December 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Innate immunity relies upon the ability of a variety of recognition molecules to sense pathogens through conserved molecular signatures that are often carbohydrates. Ficolins are oligomeric proteins assembled from collagen-like stalks and fibrinogen-like domains that have the ability to sense these molecular patterns on both pathogens and apoptotic cell surfaces. Three ficolins, termed L, H and M, have been identified in humans. They differ in their localization and concentration in extracellular fluids, their mode of secretion and their recognition properties. From a structural point of view, ficolins are assembled from basal trimeric subunits comprising a collagen-like triple helix and a globular domain composed of 3 fibrinogen-like domains. The globular domains are responsible for sensing danger signals whereas the collagen-like stalks provide a link with immune effectors. This review mainly focuses on the structure and recognition properties of the 3 human ficolins, as revealed by recent crystallographic analysis of their recognition domains. The ligand binding sites have been identified in the 3 ficolins and their recognition mechanisms have been characterized at the atomic level. In the case of M-ficolin, a structural transition at acidic pH disables the binding pocket, and thus likely participates in the functional cycle of this protein.



 goto top of outline Author Contacts

Dr. Christine Gaboriaud
Institut de Biologie Structurale JP Ebel
41 rue Jules Horowitz
FR–38041 Grenoble Cedex 1 (France)
Tel. +33 4 3878 9599, Fax +33 4 3878 5122, E-Mail christine.gaboriaud@ibs.fr


 goto top of outline Article Information

Received: February 25, 2009
Accepted after revision: May 26, 2009
Published online: August 6, 2009
Number of Print Pages : 7
Number of Figures : 3, Number of Tables : 0, Number of References : 31


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 2, No. 1, Year 2010 (Cover Date: December 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Medzhitov R: Recognition of microorganisms and activation of the immune response. Nature 2007;449:819–826.
  2. Fujita T, Matsushita M, Endo Y: The lectin-complement pathway: its role in innate immunity and evolution. Immunol Rev 2004;198:185–202.
  3. Matsushita M, Endo Y, Taira S, Sato Y, Fujita T, Ichikawa N, Nakata M, Mizuochi T: A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin. J Biol Chem 1996;271:2448–2454.
  4. Sugimoto R, Yae Y, Akaiwa M, Kitajima S, Shibata Y, Sato H, Hirata J, Okochi K, Izuhara K, Hamasaki N: Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J Biol Chem 1998;273:20721–20727.
  5. Harumiya S, Takeda K, Sugiura T, Fukumoto Y, Tachikawa H, Miyazono K, Fujimoto D, Ichijo H: Characterization of ficolins as novel elastin-binding proteins and molecular cloning of human ficolin-1. J Biochem (Tokyo) 1996;120:745–751.
  6. Honoré C, Rørvig S, Munthe-Fog L, Hummelshøj T, Madsen HO, Borregaard N, Garred P: The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 2008;45:2782–2789.
  7. Krarup A, Thiel S, Hansen A, Fujita T, Jensenius JC: L-ficolin is a pattern recognition molecule specific for acetyl groups. J Biol Chem 2004;279:47513–47519.
  8. Lynch NJ, Roscher S, Hartung T, Morath S, Matsushita M, Maennel DN, Kuraya M, Fujita T, Schwaeble WJ: L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J Immunol 2004;172:1198–1202.
  9. Ma YG, Cho MY, Zhao M, Park JW, Matsushita M, Fujita T, Lee BL: Human mannose-binding lectin and L-ficolin function as specific pattern recognition proteins in the lectin activation pathway of complement. J Biol Chem 2004;279:25307–25312.
  10. Aoyagi Y, Adderson EE, Min JG, Matsushita M, Fujita T, Takahashi S, Okuwaki Y, Bohnsack JF: Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B Streptococci. J Immunol 2005;174:418–425.
  11. Tsujimura M, Ishida C, Sagara Y, Miyazaki T, Murakami K, Shiraki H, Okochi K, Maeda Y: Detection of serum thermolabile beta-2 macroglycoprotein (Hakata antigen) by enzyme-linked immunosorbent assay using polysaccharide produced by Aerococcus viridans. Clin Diagn Lab Immunol 2001;8:454–459.
  12. Lacroix M, Dumestre-Pérard C, Schoehn G, Houen G, Cesbron J-Y, Arlaud GJ, Thielens NM: Residue Lys57 in the collagenous region of human L-ficolin and its counterpart Lys47 in H-ficolin play a key role in the interaction with the MASPs and the collectin receptor calreticulin. J Immunol 2009;182:456–465.
  13. Liu Y, Endo Y, Iwaki D, Nakata M, Matsushita M, Wada I, Inoue K, Munakata M, Fujita T: Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 2005;175:3150–3156.
  14. Frederiksen PD, Thiel S, Larsen CB, Jensenius JC: M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 2005;62:462–473.
  15. Teh C, Le Y, Lee SH, 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 2000;101:225–232.
  16. Matsushita M, Fujita T: Ficolins and the lectin complement pathway. Immunol Rev 2001;180:78–85.
  17. Thiel S, Vorup-Jensen T, Stover CM, Schwaeble W, Laursen SB, Poulsen K, Willis AC, Eggleton P, Hansen S, Holmskov U, Reid KB, Jensenius JC: A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997;386:506–510.
  18. Pagh R, Duus K, Laursen I, Hansen PR, Thielens N, Arlaud GJ, Kongerslev L, Højrup P, Houen G: The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with MBL through the binding site for MBL-associated serine proteases. FEBS J 2008;275:515–526.
  19. Matsushita M, Fujita T: Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med 1992;176:1497–1502.
  20. Dahl MR, Thiel S, Matsushita M, Fujita T, Willis AC, Christensen T, Vorup-Jensen T, Jensenius JC: MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 2001;15:127–135.
  21. Stover CM, Thiel S, Thelen M, Lynch NJ, Vorup-Jensen T, Jensenius JC, Schwaeble W: Two constituents of the initiation complex of the mannan-binding lectin activation pathway of complement are encoded by a single structural gene. J Immunol 1999;162:3481–3490.
  22. Takahashi M, Endo Y, Fujita T, Matsushita M: A truncated form of mannose-binding lectin-associated serine protease (MASP)-2 expressed by alternative polyadenylation is a component of the lectin complement pathway. Int Immunol 1999;11:859–863.
  23. Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C: Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 2007;26:623–633.
  24. Garlatti V, Martin L, Gout E, Reiser JB, Fujita T, Arlaud GJ, Thielens NM, Gaboriaud C: Structural sensing by M-ficolins and its control by a pH-dependent conformational switch. J Biol Chem 2007;282:35814–35820.
  25. Tanio M, Kondo S, Sugio S, Kohno T: Trivalent recognition unit of innate immunity system: crystal structure of trimeric human M-ficolin fibrinogen-like domain. J Biol Chem 2007;282:3889–3895.
  26. Kairies N, Beisel HG, Fuentes-Prior P, Tsuda R, Muta T, Iwanaga S, Bode W, Huber R, Kawabata SI: The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems. Proc Natl Acad Sci USA 2001;98:13519–13524.
  27. Gaboriaud C, Juanhuix J, Gruez A, Lacroix M, Darnault C, Pignol D, Verger D, Fontecilla-Camps JC, Arlaud GJ: The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 2003;278:46974–46982.
  28. Sheriff S, Chang CY, Ezekowitz AB: Human mannose-binding protein carbohydrate recognition domain trimerizes through a triple a-helical coiled-coil. Nat Struct Biol 1994;1:789–794.
  29. Tanio M, Kohno T: Histidine-regulated activity of M-ficolin. Biochem J 2009;417:485–491.
  30. Kählig H, Kolarich D, Zayni S, Scheberl A, Kosma P, Schaffer C, Messner P: N-acetylmuramic acid as capping element of alpha-D-fucose-containing S-layer glycoprotein glycans from Geobacillus tepidamans GS5-97T. J Biol Chem2005;280:20292–20299.
  31. Bilyy R, Stoika R: Search for novel cell surface markers of apoptotic cells. Autoimmunity 2007;40:249–253.