Mannose-binding lectin (MBL), also called mannose-binding protein or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity.[1][2]
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MBL has an oligomeric structure (400-700 kDa), built of subunits that contain three presumably identical peptide chains of about 30 kDa each.
Although MBL can form several oligomeric forms, there are indications that dimers and trimers are not biologically active and at least a tetramer form is needed for activation of complement.[3]
Human MBL2 gene is located on chromosome 10q11.2-q21.[4] Mice have two homologous genes, but in human the first of them was lost. A low level expression of an MBL1 pseudogene 1 (MBL1P1) was detected in liver. The pseudogene encodes a truncated 51-amino acid protein that is homologous to the MBLA isoform in rodents and some primates.[5]
Structural mutations in exon 1 of the human MBL2 gene, at codon 52 (Arg to Cys, allele D), codon 54 (Gly to Asp, allele B) and codon 57 (Gly to Glu, allele C), also independently reduce the level of functional serum MBL by disrupting the collagenous structure of the protein.[6] Furthermore, several nucleotide substitutions in the promoter region of the MBL2 gene at position −550 (H/L polymorphism), −221 (X/Y polymorphism) and −427, −349, −336, del (−324 to −329), −70 and +4 (P/Q polymorphisms) affect the MBL serum concentration. Both the frequency of structural mutations and the promoter polymorphisms that are in strong linkage disequilibrium vary among ethnic groups resulting in seven major haplotypes: HYPA, LYQA, LYPA, LXPA, LYPB, LYQC and HYPD. Differences in the distribution of these haplotypes are the major cause of interracial variations in MBL serum levels. Both HYPA and LYQA are high-producing haplotypes, LYPA intermediate-producing haplotype and LXPA low-producing haplotype, whereas LYPB, LYQC and HYPD are defective haplotypes, which cause a severe MBL deficiency.[7]
Both MBL2 and MBL1P1 genes has been repeatedly hit throughout evolution of primates. The latter silenced eventually by mutations in the glycine residues of the collagen-like region. It has been selectively turned off during evolution through the same molecular mechanisms causing the MBL2 variant alleles in man, suggesting an evolutionary selection for low-producing MBL genes.[6]
In rat hepatocytes, MBL is synthesized in the rough endoplasmic reticulum. While in Golgi, it undergoes two distinct posttranslational modifications and is assembled into high molecular weight multimeric complexes. The modifications produce MBL multiple forms of slightly various molecular masses and pI from 5.7 to 6.2.[8] Besides of proteolytic cleavage resulted in removal of 20-aa N-terminal signal peptide,[9] hydroxylation and glycosylation were also detected.[8] What's more, some Cys residues can be converted to dehydroalanin. [10]
MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune host. MBL recognizes carbohydrate patterns, found on the surface of a large number of pathogenic micro-organisms, including bacteria, viruses, protozoa and fungi. Binding of MBL to a micro-organism results in activation of the lectin pathway of the complement system.
Another important function of MBL is that this molecule binds apoptotic cells and enhances engulfment of whole, intact apoptotic cells, as well as cell debris by phagocytes.[11][12]
The complement system can be activated through three pathways the classical pathway, the alternative pathway, and the mannose-binding (MB) lectin pathway. The most-recently discovered mannose-binding lectin pathway activates complement through the mannose-binding lectin protein. MBL binds to carbohydrates (to be specific, mannose and fucose residues) found on the surface of many pathogens.
For example, MBL has been show to bind to:
MBL in the blood is complexed with (bound to) another protein, a serine protease called MASP-2 (MBL-associated serine protease).
In order to activate the complement system when MBL binds to its target (for example, mannose on the surface of a bacterium), the MASP protein functions to cleave the blood protein C4 into C4a and C4b. The C4b fragments can then bind to the surface of the bacterium, and initiate the formation of a C3 convertase.
The subsequent complement cascade catalyzed by C3 convertase results in creating a membrane attack complex, which causes lysis of the pathogen that MBL bound to.
It is produced in the liver as a response to infection, and is part of many other factors termed acute phase proteins.[15] Expression and function in other organs were also suggested.[16]
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