Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by many epithelial tissues in vertebrates. They bind to pathogens as part of the immune system. Overexpression of the mucin proteins, especially MUC1 is associated with many types of cancer.[1]
Although some mucins are membrane-bound due to the presence of a hydrophobic membrane-spanning domain that favors retention in the plasma membrane, most mucins are secreted onto mucosal surfaces or secreted to become a component of saliva.
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Genes
At least 19 human mucin genes have been distinguished by cDNA cloning — MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, and MUC20. [2]
The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but also in the airway.
Protein structure
Mature 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 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..
Glycosylation and aggregation
Mucin genes encode mucin monomers that are synthesized as rod-shape 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. [3] 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. [4] [5]
Clinical significance
Increased mucin production occurs in many adenocarcinomas, including cancer of the pancreas, lung, breast, ovary, colon, etc. Mucins are also overexpressed in lung diseases such as asthma, bronchitis, COPD or cystic fibrosis. Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in the disease process.[6][7][8] Moreover, mucins are also being investigated for their potential as diagnostic markers.
References
- ^ Niv Y (April 2008). "MUC1 and colorectal cancer pathophysiology considerations". World J. Gastroenterol. 14 (14): 2139–41. PMID 18407586.
- ^ Perez-Vilar, J; Hill, RL (2004). "Mucin Family of Glycoproteins". Encyclopedia of Biological Chemistry (Lennarz & Lane, EDs.) (Oxford: Academic Press/Elsevier) 2: 758-764.
- ^ Li, Y; Martin, LD; Spizz, G; Adler, KB (November 2 2001). "MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro". J Biol Chem 276 (44): 40982-90.
- ^ Rogers, DF (September 2007). "Physiology of airway mucus secretion and pathophysiology of hypersecretion". Respir Care 52 (9): 1134-1146.
- ^ Perez-Vilar, J (20087). "Mucin granule intraluminal organization". Am J Respir Cell Mol Biol 36: 183-190.
- ^ Singh, A.P. et al. "Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis." Cancer Research 2004 Jan 15;64(2):622-30. PMID 14744777
- ^ Singh, A.P. et al. "Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas". Prostate. 2006 Mar 1;66(4):421-9. PMID 16302265
- ^ Singh, A.P. et al. "Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy." Cancer Research 2007 Jan 15, 67(2):433-6. PMID 17234748
- Ali, M.S., et al. "Major secretory mucin expression in chronic sinusitis." Otolaryngol Head Neck Surg. 2005 Sep; 133(3); 423-8. PMID 16143194
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