Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins are distinguished between membrane-bound mucins, forming the glycocalyx, or secreted mucins, forming mucus-gels. These mucus gels cover the wet epithelium, serving functions from lubrication (as seen e.g. in the eyes), to physico-chemical barrier formation, protecting against foreign particles and pathogens as seen in e.g. the lungs or intestine. Next to their physical properties, gel-forming and transmembrane mucins alike are also involved in cell signalling and immune responses. They often take an inhibitory role. Some mucins are associated with controlling mineralization, including nacre formation in mollusks, calcification in echinoderms and bone formation in vertebrates. Besides their physicochemical barrier properties, mucins have been reported to function as receptors for various pathogens, facilitating their invasion into host cells. Thus they display a dual role in host defence, which is currently under investigation. Dysregulation of mucin expression and secretion is closely associated with various diseases. Overexpression of the mucin proteins, especially MUC1, is associated with many types of cancer. An impaired mucus barrier integrity, showing decreased mucus layer thickness and, or increased permeability are closely linked to e.g. Crohn´s disease and Ulcerative colitis.
Human mucins Human mucins include genes with the HUGO symbol MUC 1 through 22. Of these mucins, the following classes have been defined by localization:
Secreted mucins in humans, with their chromosomal location, repeat size in amino acids (aa), whether they are gel-forming (Y) or not (N), and their tissue expression.
Membrane-bound (transmembrane) mucins: MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC21 (formerly C6orf205), MUC22 (highly polymorphic) The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but also in the airway. MUC7 is the major salivary protein.
Protein structure Mature mammalian mucins are composed of two distinct regions:
The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines. The cysteine residues participate in establishing disulfide linkages within and among mucin monomers. A large central region ("PTS domain") formed of multiple tandem repeats of 10 to 80 residue sequences in which up to half of the amino acids are serine or threonine. This area becomes saturated with hundreds of O-linked oligosaccharides. N-linked oligosaccharides are also found on mucins, but in less abundance than O-linked sugars.
Evolutionary classification The functional classification does not correspond to an exact evolutionary relationship, which is still incomplete and ongoing. Known-related groups include:
The gel-forming mucins (2, 5AC, 5B, 6, 19) are related both to each other and to otogelin and von Willebrand Factor (PTHR11339). Four of these occur in a well-conserved gene cluster (at 11p15.5 in humans). The EGF-like domain containing mucins. These include MUC3(A,B), MUC4, MUC12, MUC13, and MUC17. Some EGF-like mucins, plus MUC1 and MUC16, carry SEA domains, a vertebrate invention. It is unclear whether this points to a common origin among these transmembrane mucins. MUC21 and MUC22 are related to each other by sharing a C-terminal domain (PF14654). They also occur in a human gene cluster on 6p21.33. MUC7 is a recent invention in placental mammals. It started as a copy in the secretory calcium-binding phosphoprotein (SCPP) gene cluster and rapidly gained PTS repeats.
Function in humans Mucins have been found to have important functions in defense against bacterial and fungal infections. MUC5B, the predominant mucin in the mouth and female genital tract, has been shown to significantly reduce attachment and biofilm formation of Streptococcus mutans, a bacterium with the potential to form cavities. Unusually, MUC5B does not kill the bacteria but rather maintains it in the planktonic (non-biofilm) phase, thus maintaining a diverse and healthy oral microbiome. Similar effects of MUC5B and other mucins have been demonstrated with other pathogens, such as Candida albicans, Helicobacter pylori, and even HIV. In the mouth, mucins can also recruit anti-microbial proteins such as statherins and histatine 1, which further reduces risk of infection. Eleven mucins are expressed by the eye surface epithelia, goblet cells and associated glands, even though most of them are expressed at very low levels. They maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world.
Glycosylation and aggregation Mucin genes encode mucin monomers that are synthesized as rod-shaped apomucin cores that are post-translationally modified by exceptionally abundant glycosylation. The dense "sugar coating" of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers. Mucins are secreted as massive aggregates of proteins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulfide bonds may also play a role in this process.
Secretion Upon stimulation, MARCKS (myristylated alanine-rich C kinase substrate) protein coordinates the secretion of mucin from mucin-filled vesicles within the specialized epithelial cells. Fusion of the vesicles to the plasma membrane causes release of the mucin, which as it exchanges Ca2+ for Na+ expands up to 600 fold. The result is a viscoelastic product of interwoven molecules which, combined with other secretions (e.g., from the airway epithelium and the submucosal glands in the respiratory system), is called mucus.
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