Elsevier

Molecular Immunology

Volume 56, Issue 3, 15 December 2013, Pages 222-231
Molecular Immunology

Review
Toward a structure-based comprehension of the lectin pathway of complement

https://doi.org/10.1016/j.molimm.2013.05.220Get rights and content

Abstract

To initiate the lectin pathway of complement pattern recognition molecules bind to surface-linked carbohydrates or acetyl groups on pathogens or damaged self-tissue. This leads to activation of the serine proteases MASP-1 and MASP-2 resulting in deposition of C4 on the activator and assembly of the C3 convertase. In addition MASP-3 and the non-catalytic MAp19 and MAp44 presumably play regulatory functions, but the exact function of the MASP-3 protease remains to be established. Recent functional studies have significantly advanced our understanding of the molecular events occurring as activation progresses from pattern recognition to convertase assembly. Furthermore, atomic structures derived by crystallography or solution scattering of most proteins acting in the lectin pathway and two key complexes have become available. Here we integrate the current functional and structural knowledge concerning the lectin pathway proteins and derive overall models for their glycan bound complexes. These models are used to discuss cis- versus trans-activation of MASP proteases and the geometry of C4 deposition occurring on glycans in the lectin pathway.

Introduction

Many immunological mechanisms have evolved to defend the body toward infections and for maintenance of homeostasis in the body. Thus many cells and molecules are taking part in the anti-microbial defence systems and at the same time are involved in the removal of apoptotic or necrotic cells and tissue components. The complement system is an integral part of the innate immune system formed by more than 50 proteins. Its activation triggers a proteolytic cascade eliciting a number of immunological effector functions including the enhancement of phagocytosis, the recruitment of inflammatory cells, the formation of pores in membranes and further an instructive role on a following adaptive immune response (Ricklin et al., 2010). Complement may be activated through the alternative, the classical, and the lectin pathways; here we focus on activation through the lectin pathway (LP). The principal players of the LP are the recognition molecules: The collectins mannan-binding lectin (MBL), collectin K-1 (CL-K1), and the three ficolins (H-ficolin, L-ficolin and M-ficolin) (Fig. 1). Associated with these are three proteases: the MBL associated serine proteases (MASPs) MASP-1, MASP-2 and MASP-3 and the two MBL associated proteins MAp19 (also known as sMAP) and MAp44 (also called MAP-1) (Yongqing et al., 2012).

Section snippets

The pattern recognition molecules

MBL and CL-K1 belongs to the collectin family, a family also encompassing the surfactant proteins of the lung (SP-A and SP-D), collectin L-1 (CL-L1, also named collectin 11) and the membrane bound long placental collectin-P1 (CL-P1) (Veldhuizen et al., 2011). Collectins are characterized by a collagen-like region and a C-type carbohydrate recognition domain (CRD) in their C-terminal end (Fig. 2A). Such a C-type CRD specifically recognizes a monosaccharide exposing horizontal 3′- and 4′-OH

Mannan-binding lectin associated serine proteases and proteins

The most well-established role of the recognition molecules is their association with five MBL associated serine proteases and proteins originating from two genes. MASP-1, MASP-3 and MAp44 are alternative splice products from the MASP1 gene (Dahl et al., 2001, Degn et al., 2009, Takada et al., 1993), while MASP-2 and MAp19 are alternative splice products from the MASP2 gene (Stover et al., 1999). MASP-1, -2 and -3 contain two CUB, one EGF, two CCP and the catalytic SP domain (Fig. 2B). The

The architecture of the pattern recognition molecules

A trimer of MBL is the basic building block that is organized in oligomers ranging from dimers to octamers. Studies with electron microscopy and atomic force microscopy (Jensenius et al., 2009, Lu et al., 1990) suggested that these oligomers are assembled through the Cys-rich N-terminal region from which the collagen stems and the CRDs protrude to form near-planar oligomers or more three dimensional bouquets, which is also the case for ficolins (Gout et al., 2011, Lacroix et al., 2009). Small

The structural basis for cleavage of C4 by MASP-2

A major step forward toward understanding in structural details how complement activation occurs through the lectin pathway was recently made with our structure of the complex between human complement C4 and a CCP1-CCP2-SP fragment of MASP-2 (Fig. 3A and B) where the catalytic triad serine was substituted with an alanine (Kidmose et al., 2012).

Conclusion and outlook

Activation of the complement system is a strong inflammatory response toward infections or toward damaged cells or tissues. On one hand this leads to protection but on the other hand it may have fatal outcome if the inflammation generating processes are not properly controlled by host complement inhibitors. It is thus important to unravel the mechanisms leading to complement activation. In the present report we suggest a model for the activation via MBL/MASP complexes. Although a complete

Acknowledgements

We are grateful to S. Degn, R.T. Kidmose and C. Gaboriaud for discussions. Our work was supported by the Lundbeck Foundation. GRA was further supported through a Hallas-Møller stipend from the Novo-Nordisk Foundation and the LUNA Nanomedicine Center.

References (116)

  • A.R. Gingras et al.

    Structural basis of mannan-binding lectin recognition by its associated serine protease MASP-1: implications for complement activation

    Structure

    (2011)
  • E. Gout et al.

    Carbohydrate recognition properties of human ficolins: glycan array screening reveals the sialic acid binding specificity of M-ficolin

    J. Biol. Chem.

    (2010)
  • L.A. Gregory et al.

    The X-ray structure of human mannan-binding lectin-associated protein 19 (MAp19) and its interaction site with mannan-binding lectin and L-ficolin

    J. Biol. Chem.

    (2004)
  • V. Harmat et al.

    The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions

    J. Mol. Biol.

    (2004)
  • H. Jensenius et al.

    Mannan-binding lectin: structure, oligomerization, and flexibility studied by atomic force microscopy

    J. Mol. Biol.

    (2009)
  • I. Kang et al.

    Mannan-binding lectin (MBL)-associated plasma protein present in human urine inhibits calcium oxalate crystal growth

    FEBS Lett.

    (1999)
  • A. Krarup et al.

    L-ficolin is a pattern recognition molecule specific for acetyl groups

    J. Biol. Chem.

    (2004)
  • A. Krarup et al.

    Recognition of acetylated oligosaccharides by human L-ficolin

    Immunol. Lett.

    (2008)
  • M. Kuraya et al.

    Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation

    Immunobiology

    (2005)
  • Y. Le et al.

    Human L-ficolin: plasma levels, sugar specificity, and assignment of its lectin activity to the fibrinogen-like (FBG) domain

    FEBS Lett.

    (1998)
  • Y.J. Ma et al.

    Synergy between ficolin-2 and pentraxin 3 boosts innate immune recognition and complement deposition

    J. Biol. Chem.

    (2009)
  • M. Matsushita et al.

    Cleavage of the third component of complement (C3) by mannose-binding protein-associated serine protease (MASP) with subsequent complement activation

    Immunobiology

    (1995)
  • M. Matsushita et al.

    A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin

    J. Biol. Chem.

    (1996)
  • M. Megyeri et al.

    Quantitative characterization of the activation steps of mannan-binding lectin (MBL)-associated serine proteases (MASPs) points to the central role of MASP-1 in the initiation of the complement lectin pathway

    J. Biol. Chem.

    (2013)
  • A. Miller et al.

    Near-planar solution structures of mannose-binding lectin oligomers provide insight on activation of lectin pathway of complement

    J. Biol. Chem.

    (2012)
  • H.V. Olesen et al.

    The mannan-binding lectin pathway and lung disease in cystic fibrosis – disfunction of mannan-binding lectin-associated serine protease 2 (MASP-2) may be a major modifier

    Clin. Immunol.

    (2006)
  • V. Rossi et al.

    Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2

    J. Biol. Chem.

    (2001)
  • V. Rossi et al.

    Functional characterization of complement proteases C1s/mannan-binding lectin-associated serine protease-2 (MASP-2) chimeras reveals the higher C4 recognition efficacy of the MASP-2 complement control protein modules

    J. Biol. Chem.

    (2005)
  • A. Sirmaci et al.

    MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes

    Am. J. Hum. Genet.

    (2010)
  • M.O. Skjoedt et al.

    A novel mannose-binding lectin/ficolin-associated protein is highly expressed in heart and skeletal muscle tissues and inhibits complement activation

    J. Biol. Chem.

    (2010)
  • M.O. Skjoedt et al.

    Crystal structure and functional characterization of the complement regulator mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1)

    J. Biol. Chem.

    (2012)
  • R. Steffensen et al.

    Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers

    J. Immunol. Methods

    (2000)
  • R. Sugimoto et al.

    Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family

    J. Biol. Chem.

    (1998)
  • F. Takada et al.

    A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum

    Biochem. Biophys. Res. Commun.

    (1993)
  • M. Tanio et al.

    Trivalent recognition unit of innate immunity system: crystal structure of trimeric human M-ficolin fibrinogen-like domain

    J. Biol. Chem.

    (2007)
  • F. Teillet et al.

    Crystal structure of the CUB1-EGF-CUB2 domain of human MASP-1/3 and identification of its interaction sites with mannan-binding lectin and ficolins

    J. Biol. Chem.

    (2008)
  • A.J. Tenner et al.

    Mannose binding protein (MBP) enhances mononuclear phagocyte function via a receptor that contains the 126,000 M(r) component of the C1q receptor

    Immunity

    (1995)
  • Y.M. Ali et al.

    The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection

    PLoS Pathog.

    (2012)
  • G. Ambrus et al.

    Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments

    J. Immunol.

    (2003)
  • C.B. Andersen et al.

    Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes

    Nature

    (2010)
  • Y. Aoyagi et al.

    Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B streptococci

    J. Immunol.

    (2005)
  • Y. Aoyagi et al.

    L-Ficolin/mannose-binding lectin-associated serine protease complexes bind to group B streptococci primarily through N-acetylneuraminic acid of capsular polysaccharide and activate the complement pathway

    Infect. Immun.

    (2008)
  • S. Cestari Idos et al.

    Role of early lectin pathway activation in the complement-mediated killing of Trypanosoma cruzi

    Mol. Immunol.

    (2009)
  • S.E. Degn et al.

    MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation

    J. Immunol.

    (2009)
  • S.E. Degn et al.

    Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function

    J. Immunol.

    (2012)
  • J. Dobo et al.

    MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity

    J. Immunol.

    (2009)
  • J. Dobo et al.

    Cleavage of kininogen and subsequent bradykinin release by the complement component: mannose-binding lectin-associated serine protease (MASP)-1

    PLoS One

    (2011)
  • K. Duus et al.

    CD91 interacts with mannan-binding lectin (MBL) through the MBL-associated serine protease-binding site

    FEBS J.

    (2010)
  • H. Feinberg et al.

    Crystal structure of the CUB1-EGF-CUB2 region of mannose-binding protein associated serine protease-2

    EMBO J.

    (2003)
  • V. Garlatti et al.

    Structural insights into the innate immune recognition specificities of L- and H-ficolins

    EMBO J.

    (2007)
  • Cited by (53)

    • The Complement System

      2018, The Complement FactsBook: Second Edition
    • Complement: A primer for the coming therapeutic revolution

      2017, Pharmacology and Therapeutics
      Citation Excerpt :

      All the enzymes that activate or control the complement pathways are serine proteases similar in structure to trypsin and chymotrypsin, and have the canonical serine protease domain catalytic triad residues (Beinrohr, Dobo, Zavodszky, & Gal, 2008; Forneris, Wu, & Gros, 2012; Gal, Dobo, Zavodszky, & Sim, 2009; Sim & Laich, 2000). The pattern recognition proteins of the classical and MBL/ficolin pathways, C1q, mannose binding protein and the ficolins and collectins, all have collagen stalks of various lengths and globular domains responsible for binding to activating ligands (Carland & Gerwick, 2010; Endo, Matsushita, & Fujita, 2011; Fujita et al., 2004; Hansen, Ohtani, Roy, & Wakamiya, 2016; Kjaer, Thiel, & Andersen, 2013). The proteins that form the MAC (C5b-9), share a domain common to an extended protein family known as the MACPF/CDC family of pore-forming toxins (Dunstone & Tweten, 2012; Rosado et al., 2008).

    View all citing articles on Scopus
    View full text