Fig. 2.18 The carbohydrate side chains on yeast and vertebrate glycoproteins are terminated with different patterns of sugars. N-linked glycosylation in fungi and animals is initiated by the addition of the same precursor oligosaccharide, Glc3Man9-GlcNAc2 (left panel), to an asparagine residue. In many yeasts this is processed to high-mannose glycans (middle panel). In contrast, in vertebrates, the initial glycan is trimmed and processed, and the N-linked glycoproteins of vertebrates have terminal sialic acid residues (right panel).
The lectin pathway can be triggered by any of four different pattern recognition receptors that circulate in blood and extracellular fluids and recognize carbohydrates on microbial surfaces. The first such receptor to be discovered was mannose-binding lectin (MBL), which is shown in Fig. 2.19, and which is synthesized in the liver. MBL is an oligomeric protein built up from a monomer that contains an amino-terminal collagen-like domain and a carboxy-terminal C-type lectin domain (see Section 2-4). Proteins of this type are called collectins. MBL monomers assemble into trimers through the formation of a triple helix by their collagen-like domains. Trimers then assemble into oligomers by disulfide bonding between the cysteine-rich collagen domains. The MBL present in the blood is composed of two to six trimers, with the major forms of human MBL being trimers and tetramers. A single carbohydrate-recognition domain of MBL has a low affinity for mannose, fucose, and N-acetylglucosamine (GlcNAc) residues, which are common on microbial glycans, but does not bind sialic acid residues, which terminate vertebrate glycans. Thus, multimeric MBL has high total binding strength, or avidity, for repetitive carbohydrate structures on a wide variety of microbial surfaces, including Gram-positive and Gram-negative bacteria, mycobacteria, yeasts, and some viruses and parasites, while not interacting with host cells. MBL is present at low concentrations in the plasma of most individuals, but in the presence of infection, its production is increased during the acute-phase response. This is part of the induced phase of the innate immune response and is discussed in Chapter 3.
The other three pathogen-recognition molecules used by the lectin pathway are known as ficolins. Although related in overall shape and function to MBL, they have a fibrinogen-like domain, rather than a lectin domain, attached to
Mannose-binding lectin (MBL) (left panels) is an oligomeric protein in which two to six clusters of carbohydrate-binding heads arise from a central stalk formed from the collagen-like tails of the MBL monomers. An MBL monomer is composed of a collagen region (red), an α-helical neck region (blue), and a carbohydrate-recognition domain (yellow). Three MBL monomers associate to form a trimer, and between two and six trimers assemble to form a mature MBL molecule (bottom left panel). An MBL molecule associates with MBL-associated serine proteases (MASPs). MBL binds to bacterial surfaces that display a particular spatial arrangement of mannose or fucose residues. The ficolins (right panels) resemble MBL in their overall structure, are associated with MASP-1 and MASP-2, and can activate C4 and C2 after binding to carbohydrate molecules present on microbial surfaces. The carbohydrate-binding domain of ficolins is a fibrinogenlike domain, rather than the lectin domain present in MBL.
Fig. 2.19 Mannose-binding lectin and ficolins form complexes with serine proteases and recognize particular carbohydrates on microbial surfaces.