enamelin

Enamelin is thought to be the oldest member of the enamel matrix protein (EMP) family, with animal studies showing remarkable conservation of the gene phylogenetically.{{cite journal | vauthors = Al-Hashimi N, Lafont AG, Delgado S, Kawasaki K, Sire JY | title = The enamelin genes in lizard, crocodile, and frog and the pseudogene in the chicken provide new insights on enamelin evolution in tetrapods | journal = Molecular Biology and Evolution | volume = 27 | issue = 9 | pages = 2078–94 | date = September 2010 | pmid = 20403965 | doi = 10.1093/molbev/msq098 | doi-access = free }} All other EMPs are derived from enamelin, such as amelogenin.{{cite journal | vauthors = Sire JY, Davit-Béal T, Delgado S, Gu X | title = The origin and evolution of enamel mineralization genes | journal = Cells Tissues Organs | volume = 186 | issue = 1 | pages = 25–48 | date = 2007 | pmid = 17627117 | doi = 10.1159/000102679 | s2cid = 38992844 }} EMPs belong to a larger family of proteins termed 'secretory calcium-binding phosphoproteins' (SCPP).{{cite journal | vauthors = Hu JC, Lertlam R, Richardson AS, Smith CE, McKee MD, Simmer JP | title = Cell proliferation and apoptosis in enamelin null mice | journal = European Journal of Oral Sciences | volume = 119 | pages = 329–37 | date = December 2011 | issue = Suppl 1 | pmid = 22243264 | pmc = 3292790 | doi = 10.1111/j.1600-0722.2011.00860.x }}

Similar to other enamel matrix proteins, enamelin undergoes extensive post-translational modifications (mainly phosphorylation), processing, and secretion by proteases. Enamelin has three putative phosphoserines (Ser⁵⁴, Ser¹⁹¹, and Ser²¹⁶ in humans) phosphorylated by a Golgi-associated secretory pathway kinase (FAM20C) based on their distinctive Ser-x-Glu (S-x-E) motifs.{{cite journal | vauthors = Yan WJ, Ma P, Tian Y, Wang JY, Qin CL, Feng JQ, Wang XF | title = The importance of a potential phosphorylation site in enamelin on enamel formation | journal = International Journal of Oral Science | volume = 9 | issue = 11 | pages = e4 | date = November 2017 | pmid = 29593332 | pmc = 5775333 | doi = 10.1038/ijos.2017.41 }} The major secretory product of the ENAM gene has 1103 amino acids (post-secretion), and has an acidic isoelectric point ranging from 4.5–6.5 (depending on the fragment).{{cite journal | vauthors = Hu JC, Yamakoshi Y | title = Enamelin and autosomal-dominant amelogenesis imperfecta | journal = Critical Reviews in Oral Biology and Medicine | volume = 14 | issue = 6 | pages = 387–98 | date = 2003 | pmid = 14656895 | doi = 10.1177/154411130301400602 | doi-access = free }}

At the secretory stage, the enzyme matrix metalloproteinase-20 (MMP20) proteolytically cleaves the secreted enamelin protein immediately upon release, into several smaller polypeptides; each having their own functions. However, the whole protein (~168 kDa) and its largest derivative fragment (~89 kDa) are undetectable in the secretory stage; these are existent only at the mineralisation front. Smaller polypeptide fragments remain embedded in the enamel, throughout the secretory stage enamel matrix. These strongly bind to the mineral and arrest seeded crystal growth.

The primary function of the proteins acts at the mineralisation front; growth sites where it is the interface between the ameloblast plasma membrane and lengthening extremity of crystals. The key activities of enamelin can be summarised:

• Necessary for the adhesion of ameloblasts to the surface of the enamel in the secretory stage{{cite book |title= Fundamentals of oral histology and physiology |last1=Hand |first1=Arthur R |last2=Frank |first2=Marion E | name-list-style = vanc |date=2014-11-21 |isbn=9781118938317 |location=Ames, Iowa |oclc=891186059 }}
• Binds to hydroxyapatite and promotes crystallite elongation
• Act as a modulator for de novo mineral formation

It is speculated that this protein could interact with amelogenin or other enamel matrix proteins and be important in determining growth of the length of enamel crystallites. The mechanism of this proposed co-interaction is synergistic ("Goldilocks effect"). With enamelin enhancing the rates of crystal nucleation via the creation of addition sites for EMPs, such as amelogenin, to template calcium phosphate nucleation.{{Cite journal| vauthors = Tao J, Fijneman A, Wan J, Prajapati S, Mukherjee K, Fernandez-Martinez A, Moradian-Oldak J, De Yoreo JJ |date=2018-12-05|title=Control of Calcium Phosphate Nucleation and Transformation through Interactions of Enamelin and Amelogenin Exhibits the "Goldilocks Effect" |journal=Crystal Growth & Design|volume=18|issue=12|pages=7391–7400|doi=10.1021/acs.cgd.8b01066 |pmid=32280310|url=https://research.tue.nl/nl/publications/control-of-calcium-phosphate-nucleation-and-transformation-through-interactions-of-enamelin-and-amelogenin-exhibits-the-goldilocks-effect(1cb6041f-11c8-415f-8c7a-86dda075be39).html|pmc=7152501}}

It is best thought to understand the overarching function of enamelin as the proteins responsible for correct enamel thickness formation.

Mutations in the ENAM gene can cause certain subtypes of amelogenesis imperfecta (AI), a heterogenous group of heritable conditions in which enamel in malformed.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/10117|title=ENAM enamelin [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2019-02-28}} Point mutations can cause autosomal-dominant hypoplastic AI, and novel ENAM mutations can cause autosomal-recessive hypoplastic AI.{{cite journal | vauthors = Pavlic A, Petelin M, Battelino T | title = Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG | journal = Archives of Oral Biology | volume = 52 | issue = 3 | pages = 209–17 | date = March 2007 | pmid = 17125728 | doi = 10.1016/j.archoralbio.2006.10.010 }}{{cite journal | vauthors = Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, Ozdemir D, Firatli S, Aren G, Firatli E | display-authors = 6 | title = Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects | journal = Journal of Medical Genetics | volume = 40 | issue = 12 | pages = 900–6 | date = December 2003 | pmid = 14684688 | pmc = 1735344 | doi = 10.1136/jmg.40.12.900 }} However, mutations in the ENAM gene mainly tend to lead to the autosomal-dominant AI. The phenotype of the mutations are generalised thin enamel and no defined enamel layer.

A moderately higher than usual ENAM expression leads to protrusive structures (often, horizontal grooves) on the surface of enamel, and with high transgene expression, the enamel layer is almost lost.{{cite journal | vauthors = Kim JW, Seymen F, Lin BP, Kiziltan B, Gencay K, Simmer JP, Hu JC | title = ENAM mutations in autosomal-dominant amelogenesis imperfecta | journal = Journal of Dental Research | volume = 84 | issue = 3 | pages = 278–82 | date = March 2005 | pmid = 15723871 | doi = 10.1177/154405910508400314 | s2cid = 464969 }}

• Ameloblastin
• Amelogenin
• Amelogenesis
• Amelogenesis imperfecta

{{reflist|30em}}

{{refbegin|30em}}

• {{cite journal | vauthors = Gutierrez SJ, Chaves M, Torres DM, Briceño I | title = Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta | journal = Archives of Oral Biology | volume = 52 | issue = 5 | pages = 503–6 | date = May 2007 | pmid = 17316551 | doi = 10.1016/j.archoralbio.2006.09.014 }}
• {{cite journal | vauthors = Pavlic A, Petelin M, Battelino T | title = Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG | journal = Archives of Oral Biology | volume = 52 | issue = 3 | pages = 209–17 | date = March 2007 | pmid = 17125728 | doi = 10.1016/j.archoralbio.2006.10.010 }}
• {{cite journal | vauthors = Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP | title = Phosphoproteomic analysis of the developing mouse brain | journal = Molecular & Cellular Proteomics | volume = 3 | issue = 11 | pages = 1093–101 | date = November 2004 | pmid = 15345747 | doi = 10.1074/mcp.M400085-MCP200 | doi-access = free }}
• {{cite journal | vauthors = Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, Ozdemir D, Firatli S, Aren G, Firatli E | title = Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects | journal = Journal of Medical Genetics | volume = 40 | issue = 12 | pages = 900–6 | date = December 2003 | pmid = 14684688 | pmc = 1735344 | doi = 10.1136/jmg.40.12.900 }}
• {{cite journal | vauthors = Hart PS, Michalec MD, Seow WK, Hart TC, Wright JT | title = Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature | journal = Archives of Oral Biology | volume = 48 | issue = 8 | pages = 589–96 | date = August 2003 | pmid = 12828988 | doi = 10.1016/S0003-9969(03)00114-6 }}
• {{cite journal | vauthors = Kida M, Ariga T, Shirakawa T, Oguchi H, Sakiyama Y | title = Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary | journal = Journal of Dental Research | volume = 81 | issue = 11 | pages = 738–42 | date = November 2002 | pmid = 12407086 | doi = 10.1177/154405910208101103 }}
• {{cite journal | vauthors = Rajpar MH, Harley K, Laing C, Davies RM, Dixon MJ | title = Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta | journal = Human Molecular Genetics | volume = 10 | issue = 16 | pages = 1673–7 | date = August 2001 | pmid = 11487571 | doi = 10.1093/hmg/10.16.1673 | doi-access = free }}
• {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
• {{cite journal | vauthors = Dong J, Gu TT, Simmons D, MacDougall M | title = Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus | journal = European Journal of Oral Sciences | volume = 108 | issue = 5 | pages = 353–8 | date = October 2000 | pmid = 11037750 | doi = 10.1034/j.1600-0722.2000.108005353.x }}
• {{cite journal | vauthors = Hu CC, Hart TC, Dupont BR, Chen JJ, Sun X, Qian Q, Zhang CH, Jiang H, Mattern VL, Wright JT, Simmer JP | title = Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development | journal = Journal of Dental Research | volume = 79 | issue = 4 | pages = 912–9 | date = April 2000 | pmid = 10831092 | doi = 10.1177/00220345000790040501 | s2cid = 24476486 }}
• {{cite journal | vauthors = Forsman K, Lind L, Bäckman B, Westermark E, Holmgren G | title = Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q | journal = Human Molecular Genetics | volume = 3 | issue = 9 | pages = 1621–5 | date = September 1994 | pmid = 7833920 | doi = 10.1093/hmg/3.9.1621 }}

{{refend}}

• {{UCSC genome browser|ENAM}}
• {{UCSC gene details|ENAM}}

Category:Proteins

Category:Dentistry

Category:Biomineralization

Category:Teeth