ReviewToward a structure-based comprehension of the lectin pathway of complement
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.
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2017, Pharmacology and TherapeuticsCitation 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).