Enamelin

Enamelin is an enamel matrix protein (EMPs), that in humans is encoded by the ENAM gene.<ref name="pmid11978766">,

 A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2), 
 Human Molecular Genetics, 
 
 Vol. 11(Issue: 9),
 pp. 1069–74,
 DOI: 10.1093/hmg/11.9.1069,
 PMID: 11978766,</ref><ref name="entrez">

Entrez Gene: ENAM enamelin(link). {{{website}}}.

</ref> It is part of the non-amelogenins, which comprise 10% of the total enamel matrix proteins.<ref name=":0">,

 Ten Cate's Oral Histology, 
 8th edition, 
 Elsevier India, 
  
  
  
 ISBN 978-8131233436,</ref> It is one of the key proteins thought to be involved in amelogenesis (enamel development). The formation of enamel's intricate architecture is thought to be rigorously controlled in ameloblasts through interactions of various organic matrix protein molecules that include: enamelin, amelogenin, ameloblastin, tuftelin, dentine sialophosphoprotein, and a variety of enzymes. Enamelin is the largest protein (~168kDa) in the enamel matrix of developing teeth and is the least abundant (encompasses approximately 1-5%) of total enamel matrix proteins.<ref name="entrez" /> It is present predominantly at the growing enamel surface.

Structure

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.<ref>,

 The enamelin genes in lizard, crocodile, and frog and the pseudogene in the chicken provide new insights on enamelin evolution in tetrapods, 
 Molecular Biology and Evolution, 
 
 Vol. 27(Issue: 9),
 pp. 2078–94,
 DOI: 10.1093/molbev/msq098,
 PMID: 20403965,</ref> All other EMPs are derived from enamelin, such as amelogenin.<ref>, 
 The origin and evolution of enamel mineralization genes, 
 Cells Tissues Organs, 
 
 Vol. 186(Issue: 1),
 pp. 25–48,
 DOI: 10.1159/000102679,
 PMID: 17627117,</ref> EMPs belong to a larger family of proteins termed 'secretory calcium-binding phosphoproteins' (SCPP).<ref>, 
 Cell proliferation and apoptosis in enamelin null mice, 
 European Journal of Oral Sciences, 
 
 Vol. 119 Suppl 1,
 pp. 329–37,
 DOI: 10.1111/j.1600-0722.2011.00860.x,
 PMID: 22243264,
 PMC: 3292790,</ref>

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.<ref>,

 The importance of a potential phosphorylation site in enamelin on enamel formation, 
 International Journal of Oral Science, 
 
 Vol. 9(Issue: 11),
 pp. e4,
 DOI: 10.1038/ijos.2017.41,
 PMID: 29593332,
 PMC: 5775333,</ref> 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).<ref name="pmid14656895">, 
 Enamelin and autosomal-dominant amelogenesis imperfecta, 
 Critical Reviews in Oral Biology and Medicine, 
 
 Vol. 14(Issue: 6),
 pp. 387–98,
 DOI: 10.1177/154411130301400602,
 PMID: 14656895,</ref>

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.<ref name=":0" /> Smaller polypeptide fragments remain embedded in the enamel, throughout the secretory stage enamel matrix. These strongly bind to the mineral and retard seeded crystal growth.

Function

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<ref name=":1">,

 Fundamentals of oral histology and physiology, 
  
 Ames, Iowa: 
  
  
  
 ISBN 9781118938317,</ref>

• Binds to hydroxyapatite and promotes crystallite elongation
• Act as a modulator for de novo mineral formation<ref name=":0" />

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.<ref>,

 Control of Calcium Phosphate Nucleation and Transformation through Interactions of Enamelin and Amelogenin Exhibits the "Goldilocks Effect", 
 Crystal Growth & Design, 
 
 Vol. 18(Issue: 12),
 pp. 7391–7400,
 DOI: 10.1021/acs.cgd.8b01066,
 PMID: 32280310,
 PMC: 7152501,
 
 Full text,</ref>

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

Clinical significance

Mutations in the ENAM gene can cause certain subtypes of amelogenesis imperfecta (AI), a heterogenous group of heritable conditions in which enamel in malformed.<ref>

ENAM enamelin [Homo sapiens (human)] - Gene - NCBI(link). www.ncbi.nlm.nih.gov.

Accessed 2019-02-28.

</ref> Point mutations can cause autosomal-dominant hypoplastic AI, and novel ENAM mutations can cause autosomal-recessive hypoplastic AI.<ref>,

 Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG, 
 Archives of Oral Biology, 
 
 Vol. 52(Issue: 3),
 pp. 209–17,
 DOI: 10.1016/j.archoralbio.2006.10.010,
 PMID: 17125728,</ref><ref>, 
 Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects, 
 Journal of Medical Genetics, 
 
 Vol. 40(Issue: 12),
 pp. 900–6,
 DOI: 10.1136/jmg.40.12.900,
 PMID: 14684688,
 PMC: 1735344,</ref> However, mutations in the ENAM gene mainly tend to lead to the autosomal-dominant AI.<ref name=":1" /> The phenotype of the mutations are generalised thin enamel and no defined enamel layer.<ref name=":0" />

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.<ref>,

 ENAM mutations in autosomal-dominant amelogenesis imperfecta, 
 Journal of Dental Research, 
 
 Vol. 84(Issue: 3),
 pp. 278–82,
 DOI: 10.1177/154405910508400314,
 PMID: 15723871,</ref>

See also

• Ameloblastin
• Amelogenin
• Amelogenesis
• Amelogenesis imperfecta

Further reading

• ,

 Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta, 
 Archives of Oral Biology, 
 
 Vol. 52(Issue: 5),
 pp. 503–6,
 DOI: 10.1016/j.archoralbio.2006.09.014,
 PMID: 17316551,

• ,

 Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG, 
 Archives of Oral Biology, 
 
 Vol. 52(Issue: 3),
 pp. 209–17,
 DOI: 10.1016/j.archoralbio.2006.10.010,
 PMID: 17125728,

• ,

 Phosphoproteomic analysis of the developing mouse brain, 
 Molecular & Cellular Proteomics, 
 
 Vol. 3(Issue: 11),
 pp. 1093–101,
 DOI: 10.1074/mcp.M400085-MCP200,
 PMID: 15345747,

• ,

 Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects, 
 Journal of Medical Genetics, 
 
 Vol. 40(Issue: 12),
 pp. 900–6,
 DOI: 10.1136/jmg.40.12.900,
 PMID: 14684688,
 PMC: 1735344,

• ,

 Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature, 
 Archives of Oral Biology, 
 
 Vol. 48(Issue: 8),
 pp. 589–96,
 DOI: 10.1016/S0003-9969(03)00114-6,
 PMID: 12828988,

• ,

 Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary, 
 Journal of Dental Research, 
 
 Vol. 81(Issue: 11),
 pp. 738–42,
 DOI: 10.1177/154405910208101103,
 PMID: 12407086,

• ,

 Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta, 
 Human Molecular Genetics, 
 
 Vol. 10(Issue: 16),
 pp. 1673–7,
 DOI: 10.1093/hmg/10.16.1673,
 PMID: 11487571,

• ,

 DNA cloning using in vitro site-specific recombination, 
 Genome Research, 
 
 Vol. 10(Issue: 11),
 pp. 1788–95,
 DOI: 10.1101/gr.143000,
 PMID: 11076863,
 PMC: 310948,

• ,

 Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus, 
 European Journal of Oral Sciences, 
 
 Vol. 108(Issue: 5),
 pp. 353–8,
 DOI: 10.1034/j.1600-0722.2000.108005353.x,
 PMID: 11037750,

• ,

 Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development, 
 Journal of Dental Research, 
 
 Vol. 79(Issue: 4),
 pp. 912–9,
 DOI: 10.1177/00220345000790040501,
 PMID: 10831092,

• ,

 Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q, 
 Human Molecular Genetics, 
 
 Vol. 3(Issue: 9),
 pp. 1621–5,
 DOI: 10.1093/hmg/3.9.1621,
 PMID: 7833920,

External links

• Template:UCSC genome browser
• Template:UCSC gene details

Portions of content adapted from Wikipedia's article on Enamelin which is released under the CC BY-SA 3.0.