Components of Mannose Binding Lectin (MBL) Pathway and their Functions

The mannose-binding lectin (MBL) pathway activates complement cascade through

mannose-binding lectin protein to evade innate immunity. The pathway need some basic
components to activate the complement system. The basic components of mannose-binding
lectin (MBL) pathway include mannose-binding lectin (MBL), MASPs, complexes, enzymes and
formation of membrane attack complex.
Mannose Binding Lectin (MBL) is a protein that can activate complement cascade
without the presence of antibody and C1 complex. The MBL is a serum protein synthesized from
the liver. MBL can recognize wide range of microorganisms such as gram-positive and gramnegative bacteria, yeasts, parasites, mycobacteria and virus (Takahashi & Ezekowitz, 2005).
MBL is a family of proteins called collectins. It consists of collagenous domains and
lectin domains (Ip, Takahashi, Ezodyekwitz & Stuart, 2009). Cluster of genes found on the long
arm of chromosome 10 in humans encodes for collectins (Ip et al., 2009). Human serum MBL
protein has identical polypeptide chains of 32kDa. Each chain consists of cysteine rich Nterminal region, collagenous domain, neck region and a CRD at C-terminal (Ip et al., 2009).
Trimerization of these polypeptide into subunits form a larger oligomers. Human MBL made up
of dimers to hexamers of the subunits (Figure ?). It circulates as oligomers of trimers with the
highest-order of oligomer as a hexamer of trimers (Takahashi & Ezekowitz, 2005).
MASPs (MBL-associated serine proteases) are proteins that are associated with MBL
protein. MASPs are similar with C1r and C1s of the classical pathway. They have
C1r/C1s/Uegf /bone morphogenic protein 1 and many others which are highly conserved
domain structures (Takahashi et al., 2008). There are four types of MASPs, which are MASP-1,
MASP-2, MASP-3 and MAp19 (Ip et al, 2009). MASP-1 and MASP-2 are encoded by distinct
genes and have serine protease domain (Ip et al, 2009). The MASP-3 and MAp19 are
alternatively spliced products MASP-1 and MASP-2 respectively (Ip et al, 2009). Schwaeble (as
cited in Youssif et al., 2012) found MAp19 lack of serine protease domain and it regulates lectin
pathway by competing for binding of MASPs to the carbohydrate molecule. The MASPs
normally circulate as zymogens in complexes with MBL (Sorensen & Thiel, 2005).
MBL play a role in activation of complement, phagocytosis and promotion of
inflammatory responses. It occur by binding of MBL to carbohydrates moieties (N-acetylglucosamine, mannose, fucose or glucose) present on surface of pathogens (Gal & Ambrus,
2001). This induces conformational changes in MBL (Ip et al, 2009). MBL able to initiate lectin

pathway by combining with serine proteases MASPs, forming MBL-MASP complex and enter
the circulation (Ip et al, 2009). There are MASP-1 and MASP-2 that mainly involved in lectin
pathway. MASP-2 is the key enzyme of lectin pathway. The binding of MBL to the surface of
pathogen initiates the auto activation of MASP-2 which cleaves C4 and C2 to form C3
convertase, C4b2a (Hja et al., 2012). Without MASP-2, the lectin pathway cannot be activated
because only MASP-2 can efficiently trigger the complement cascade. MASP-1 also can
autoactivate and cleave C2 but not C4. Therefore no lectin pathway can occur under the activity
of MASP-1 only as MASP-2 is needed to cleave C4 (Hja et al., 2012).
The other basic components of complement proteins. The complement proteins involve
in the activation of mannose-binding lectin pathway includes C4, C2, C3 and C5. These
complexes are proenzymes and only activated when cleaved and become fragments. To
activate the complexes, activating enzymes such as C3 convertase and C5 convertase. C3
convertase will cleaves C3 into C3a and C3b. C5 convertase will cleaves C5a and C5b. Once
cleaved into fragments, the bigger fragment will initiate the formation of membrane attack
complex (MAC) that leads to lysis of the cell. On the other hand, the smaller fragments are
known as anaphylatoxins. The anaphylatoxins are fragments that produced after the activation
of complement system which act on mast cells to release histamine that promotes inflammation
besides chemotactic migration of polymorphonuclear leukocytes (Bokisch, Dierich & MullerEberhard, 1975).
Lastly is the membrane attack complex (MAC). The membrane attack complex made up
of C5b6789. They anchor on the surface of pathogens cell membrane and make a channel that
causes the internal cell moves out of the cell called cell lysis. Gram positive bacteria, which are
protected by their thick peptidoglycan layer, bacteria with a capsule or slime layer around their
cell wall, or non-enveloped viruses are less susceptible to lysis (Sridhar, 2006).

Figure ?:

Schematic
model of pattern recognition by human mannose-binding
lectins (MBLs). Micro pattern, monosaccharide binding by a single
carbohydrate recognition domain (CRD). Macro pattern, polysaccharide
binding by a dimerized MBL. Note. From The Role of the Mannose-Binding
Lectin in Innate Immunity by K. Takahashi & R.A.B. Ezekowitz, 2005,
Clinical Infectious Diseases, 41, S441.