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Mannose-binding lectin (MBL), also called mannan-binding lectin or mannan-binding protein (MBP), is a
lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar Moiety (chemistry), groups that are part of other molecules, so cause agglutination (biology), agglutination of particular cells or precipitation of glycoconjugates an ...
that is instrumental in innate immunity as an opsonin and via the lectin pathway.


Structure

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 biologically inactive as an opsonin and at least a tetramer form is needed for activation of complement.


Genes and polymorphisms

Human MBL2 gene is located on chromosome 10q11.2-q21. 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. 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. 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. Such polymorphism also present in exon 4. 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.


Posttranslational modifications

In rat
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bi ...
s, MBL is synthesized in the rough endoplasmic reticulum. While in Golgi, it undergoes two distinct
posttranslational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA ...
s and is assembled into high molecular weight multimeric complexes. The modifications produce MBL in multiple forms of slightly various molecular masses and pI from 5.7 to 6.2. Proteolytic cleavage also resulted in removal of the 20-aa N-terminal signal peptide, and hydroxylation and glycosylation were also detected. Some cysteine residues can be converted to dehydroalanin.


Function

MBL belongs to the class of collectins in the C-type
lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar Moiety (chemistry), groups that are part of other molecules, so cause agglutination (biology), agglutination of particular cells or precipitation of glycoconjugates an ...
superfamily, whose function appears to be
pattern recognition Pattern recognition is the task of assigning a class to an observation based on patterns extracted from data. While similar, pattern recognition (PR) is not to be confused with pattern machines (PM) which may possess PR capabilities but their p ...
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 Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
,
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almo ...
,
protozoa Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...
and
fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
. Binding of MBL to a
micro-organism A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...
results in activation of the lectin pathway of the
complement system The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
. Another important function of MBL is that this molecule binds senescent and apoptotic cells and enhances engulfment of whole, intact apoptotic cells, as well as cell debris by
phagocyte Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s.


Activation

The complement system can be activated through three pathways: the classical pathway, the alternative pathway, and the lectin pathway. One way the most-recently discovered lectin pathway is activated is through mannose-binding lectin protein. MBL binds to carbohydrates (to be specific, D-mannose and L-fucose residues) found on the surfaces of many pathogens. For example, MBL has been shown to bind to: *
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
s such as
Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...
*
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almo ...
such as HIV and
influenza A ''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...
* many
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
, including
Salmonella ''Salmonella'' is a genus of bacillus (shape), rod-shaped, (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two known species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' ...
and
Streptococci ''Streptococcus'' is a genus of gram-positive spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs along a sing ...
*
parasite Parasitism is a Symbiosis, close relationship between species, where one organism, the parasite, lives (at least some of the time) on or inside another organism, the Host (biology), host, causing it some harm, and is Adaptation, adapted str ...
s like
Leishmania ''Leishmania'' () is a genus of parasitic protozoans, single-celled eukaryotic organisms of the trypanosomatid group that are responsible for the disease leishmaniasis. The parasites are transmitted by sandflies of the genus '' Phlebotomus'' ...
*
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...


Complexes

MBL in the blood is complexed with (bound to) a serine protease called MASP (MBL-associated serine protease). There are three MASPs: MASP-1, MASP-2 and MASP-3, which have protease domains. There are also sMAP (also called MAp19) and MAp44, which do not have protease domains and are thought to be regulatory molecules of MASPs. MASPs also form complexes with
ficolin Ficolins are pattern recognition receptors that bind to acetyl groups present in the carbohydrates of bacterial surfaces and mediate activation of the lectin pathway of the complement cascade. Structure Ficolins (Fi+Col+Lin) are a group of oli ...
s, which are similar to MBL functionally and structurally with the exception that ficolins recognize their targets through fibrinogen-like domains, unlike MBL. 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 C3 convertase (''C4bC2b'', formerly ''C4b2a'') belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 con ...
. The subsequent complement cascade catalyzed by C3-convertase results in creating a membrane attack complex, which causes lysis of the pathogen as well as altered-self in the context of apoptotic and necrotic cells. MBL/MASP-1 complex also has thrombin-like activity (thrombin clots fibrin to initiate blood clots). Mice that genetically lack MBL or MASP-1/3 (but not MASP-2/sMAP) have prolonged bleeding time in experimental injury models, although mice are seen to be normal if there is no insult to the body.


Clinical significance

It is produced in the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
as a response to infection, and is part of many other factors termed acute phase proteins. Expression and function in other organs were also suggested. The three structural polymorphisms of exon 1 have been reported to cause susceptibility to various common infections, including
meningococcal disease Meningococcal disease is a serious infection caused by ''Neisseria meningitidis'', also known as meningococcus, a gram negative diplococcus. Meningococcal disease includes meningitis, meningococcal septicemia, or a combination of both, which c ...
. However, evidence has been presented that suggests no harmful effect of these variants with regard to mengingococcal disease. MBL deficiency is very common in humans, with approximately 10% of individuals having this deficiency.


External links

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References

{{Complement system Immune system Collectins Blood proteins Human proteins Lectins