Mucin

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Adenocarcinoma on pap test 1.jpg
Micrograph showing cells with prominent mucin-containing intracytoplasmic vacuoles. Pap stain.
Identifiers
SymbolMucin
Membranome111

Mucins (/ˈmjuːsɪn/) are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals.[1] Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signalling to forming chemical barriers.[1] They often take an inhibitory role.[1] Some mucins are associated with controlling mineralization, including nacre formation in mollusks,[2] calcification in echinoderms[3] and bone formation in vertebrates.[4] They bind to pathogens as part of the immune system. Overexpression of the mucin proteins, especially MUC1, is associated with many types of cancer.[5][6]

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 as principal components of mucus by mucous membranes or are secreted to become a component of saliva.

Genes[edit]

Human mucins include genes with the HUGO symbol MUC 1 through 22. Of these mucins, the following classes have been defined by localization:[7][8][9][10]

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.[10]

Protein structure[edit]

Mature mammalian mucins are composed of two distinct regions:[7]

Evolutionary classification[edit]

The functional classification does not correspond to an exact evolutionary relationship, which is still incomplete and ongoing.[10] 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).[12] Four of these occur in a well-conserved gene cluster (at 11p.15.5 in humans).[13]
  • The EGF-like domain containing mucins. These include MUC3(A,B), MUC4, MUC12, MUC13, and MUC17.[14]
  • 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.[12]
  • 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.[15]

Function in humans[edit]

Mucins have been found to have important functions in defense against bacterial and fungal infections. MUC5B, the predominate 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.[16] 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.[16] Similar effects of MUC5B and other mucins have been demonstrated with other pathogens, such as Candida albicans, Helicobacter pylori, and even HIV.[17][18] In the mouth, mucins can also recruit anti-microbial proteins such as statherins and histatine 1, which further reduces risk of infection.[18]

Glycosylation and aggregation[edit]

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[edit]

Upon stimulation, MARCKS (myristylated alanine-rich C kinase substrate) protein coordinates the secretion of mucin from mucin-filled vesicles within the specialized epithelial cells.[19] 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.[20] [21]

Clinical significance[edit]

Increased mucin production occurs in many adenocarcinomas, including cancers of the pancreas, lung, breast, ovary, colon and other tissues. Mucins are also overexpressed in lung diseases such as asthma, bronchitis, chronic obstructive pulmonary disease (COPD) or cystic fibrosis.[22] Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in the disease process.[23][24][25] Mucins are under investigation as possible diagnostic markers for malignancies and other disease processes in which they are most commonly over- or mis-expressed.

Abnormal deposits of mucin are responsible for the non-pitting facial edema seen in untreated hypothyroidism. This edema is seen in the pretibial area as well.[26]

Non-vertebrate mucins[edit]

Beyond the better-studied vertebrate mucins, other animals also express (not necessarily related) proteins with similar properties. These include:

See also[edit]

References[edit]

  1. ^ a b c Marin F, Luquet G, Marie B, Medakovic D (2007). Molluscan shell proteins: primary structure, origin, and evolution. Current Topics in Developmental Biology. 80. pp. 209–76. doi:10.1016/S0070-2153(07)80006-8. ISBN 9780123739148. PMID 17950376.
  2. ^ Marin F, Corstjens P, de Gaulejac B, de Vrind-De Jong E, Westbroek P (July 2000). "Mucins and molluscan calcification. Molecular characterization of mucoperlin, a novel mucin-like protein from the nacreous shell layer of the fan mussel Pinna nobilis (Bivalvia, pteriomorphia)". The Journal of Biological Chemistry. 275 (27): 20667–20675. doi:10.1074/jbc.M003006200. PMID 10770949.
  3. ^ Boskey AL (2003). "Biomineralization: an overview". Connective Tissue Research. 44 Suppl 1 (1): 5–9. doi:10.1080/713713622. PMID 12952166.
  4. ^ Midura RJ, Hascall VC (October 1996). "Bone sialoprotein--a mucin in disguise?". Glycobiology. 6 (7): 677–681. doi:10.1093/glycob/6.7.677. PMID 8953277.
  5. ^ Niv Y (April 2008). "MUC1 and colorectal cancer pathophysiology considerations". World Journal of Gastroenterology. 14 (14): 2139–2141. doi:10.3748/wjg.14.2139. PMC 2703837. PMID 18407586.
  6. ^ Brockhausen I, Melamed J (August 2021). "Mucins as anti-cancer targets: perspectives of the glycobiologist". Glycoconjugate Journal. 38 (4): 459–474. doi:10.1007/s10719-021-09986-8. PMID 33704667. S2CID 232191632.
  7. ^ a b Moniaux N, Escande F, Porchet N, Aubert JP, Batra SK (October 2001). "Structural organization and classification of the human mucin genes". Frontiers in Bioscience. 6: D1192–D1206. doi:10.2741/moniaux. PMID 11578969.
  8. ^ Perez-Vilar J, Hill RL (2004). "Mucin Family of Glycoproteins". Encyclopedia of Biological Chemistry (Lennarz & Lane, EDs.). Oxford: Academic Press/Elsevier. 2: 758–764. doi:10.1016/B0-12-443710-9/00411-7. ISBN 9780124437104.
  9. ^ Hoorens PR, Rinaldi M, Li RW, Goddeeris B, Claerebout E, Vercruysse J, Geldhof P (March 2011). "Genome wide analysis of the bovine mucin genes and their gastrointestinal transcription profile". BMC Genomics. 12: 140. doi:10.1186/1471-2164-12-140. PMC 3056801. PMID 21385362.
  10. ^ a b c Kasprzak A, Adamek A (March 2019). "Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis". International Journal of Molecular Sciences. 20 (6): 1288. doi:10.3390/ijms20061288. PMC 6471604. PMID 30875782.
  11. ^ Norman PJ, Norberg SJ, Guethlein LA, Nemat-Gorgani N, Royce T, Wroblewski EE, et al. (May 2017). "Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II". Genome Research. 27 (5): 813–823. doi:10.1101/gr.213538.116. PMC 5411776. PMID 28360230.
  12. ^ a b Lang T, Hansson GC, Samuelsson T (October 2007). "Gel-forming mucins appeared early in metazoan evolution". Proceedings of the National Academy of Sciences of the United States of America. 104 (41): 16209–16214. Bibcode:2007PNAS..10416209L. doi:10.1073/pnas.0705984104. PMC 2042186. PMID 17911254.
  13. ^ Lang T, Klasson S, Larsson E, Johansson ME, Hansson GC, Samuelsson T (August 2016). "Searching the Evolutionary Origin of Epithelial Mucus Protein Components-Mucins and FCGBP". Molecular Biology and Evolution. 33 (8): 1921–1936. doi:10.1093/molbev/msw066. PMC 4948705. PMID 27189557.
  14. ^ Liberelle M, Jonckheere N, Melnyk P, Van Seuningen I, Lebègue N (May 2020). "EGF-Containing Membrane-Bound Mucins: A Hidden ErbB2 Targeting Pathway?". Journal of Medicinal Chemistry. 63 (10): 5074–5088. doi:10.1021/acs.jmedchem.9b02001. PMID 32027502. S2CID 211044898.
  15. ^ Xu D, Pavlidis P, Thamadilok S, Redwood E, Fox S, Blekhman R, et al. (August 2016). "Recent evolution of the salivary mucin MUC7". Scientific Reports. 6 (1): 31791. Bibcode:2016NatSR...631791X. doi:10.1038/srep31791. PMC 4997351. PMID 27558399.
  16. ^ a b Frenkel ES, Ribbeck K (January 2015). "Salivary mucins protect surfaces from colonization by cariogenic bacteria". Applied and Environmental Microbiology. 81 (1): 332–338. Bibcode:2015ApEnM..81..332F. doi:10.1128/aem.02573-14. PMC 4272720. PMID 25344244.
  17. ^ Kavanaugh NL, Zhang AQ, Nobile CJ, Johnson AD, Ribbeck K (November 2014). Berman J (ed.). "Mucins suppress virulence traits of Candida albicans". mBio. 5 (6): e01911. doi:10.1128/mBio.01911-14. PMC 4235211. PMID 25389175.
  18. ^ a b Frenkel ES, Ribbeck K (January 2015). "Salivary mucins in host defense and disease prevention". Journal of Oral Microbiology. 7 (1): 29759. doi:10.3402/jom.v7.29759. PMC 4689954. PMID 26701274.
  19. ^ Li Y, Martin LD, Spizz G, Adler KB (November 2001). "MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro". The Journal of Biological Chemistry. 276 (44): 40982–40990. doi:10.1074/jbc.M105614200. PMID 11533058.
  20. ^ Rogers DF (September 2007). "Physiology of airway mucus secretion and pathophysiology of hypersecretion". Respiratory Care. 52 (9): 1134–46, discussion 1146–9. PMID 17716382.
  21. ^ Perez-Vilar J (February 2007). "Mucin granule intraluminal organization". American Journal of Respiratory Cell and Molecular Biology. 36 (2): 183–190. doi:10.1165/rcmb.2006-0291TR. PMC 2176109. PMID 16960124.
  22. ^ Morrison CB, Markovetz MR, Ehre C (November 2019). "Mucus, mucins, and cystic fibrosis". Pediatric Pulmonology. 54 Suppl 3 (Suppl 3): S84–S96. doi:10.1002/ppul.24530. PMC 6853602. PMID 31715083.
  23. ^ Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK (January 2004). "Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis". Cancer Research. 64 (2): 622–630. doi:10.1158/0008-5472.CAN-03-2636. PMID 14744777.
  24. ^ Singh AP, Chauhan SC, Bafna S, Johansson SL, Smith LM, Moniaux N, et al. (March 2006). "Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas". The Prostate. 66 (4): 421–429. doi:10.1002/pros.20372. PMID 16302265. S2CID 21904013.
  25. ^ Singh AP, Chaturvedi P, Batra SK (January 2007). "Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy". Cancer Research. 67 (2): 433–436. doi:10.1158/0008-5472.CAN-06-3114. PMID 17234748.
  26. ^ Hanberg, Allen "Medical Surgical Nursing: clinical management for positive outcomes" Black and Hawk (Eds.). ElSevier 2009.
  27. ^ Syed ZA, Härd T, Uv A, van Dijk-Härd IF (August 2008). "A potential role for Drosophila mucins in development and physiology". PLOS ONE. 3 (8): e3041. Bibcode:2008PLoSO...3.3041S. doi:10.1371/journal.pone.0003041. PMC 2515642. PMID 18725942.
  28. ^ Cámara ML, Balouz V, Centeno Cameán C, Cori CR, Kashiwagi GA, Gil SA, et al. (May 2019). "Trypanosoma cruzi surface mucins are involved in the attachment to the Triatoma infestans rectal ampoule". PLOS Neglected Tropical Diseases. 13 (5): e0007418. doi:10.1371/journal.pntd.0007418. PMC 6544316. PMID 31107901.

Further reading[edit]

External links[edit]