Enamelin

ENAM
Identifiers
Aliases	ENAM, AIH2, AI1C, ADAI, enamelin
External IDs	OMIM: 606585; MGI: 1333772; HomoloGene: 9698; GeneCards: ENAM; OMA:ENAM - orthologs
Gene location (Human) Chr. Chromosome 4 (human) Band 4q13.3 Start 70,628,744 bp End 70,646,824 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 E1 Start 88,635,834 bp End 88,653,908 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans vastus lateralis muscle striated muscle tissue biceps brachii kidney deltoid muscle corpus epididymis gallbladder gastrocnemius muscle left ventricle Top expressed in molar tracheobronchial tree intestinal villus inferior colliculus superior colliculus primary motor cortex medulla oblongata More reference expression data BioGPS n/a
Gene ontology Molecular function structural constituent of tooth enamel protein binding Cellular component extracellular region endoplasmic reticulum lumen extracellular matrix Biological process odontogenesis of dentin-containing tooth biomineral tissue development amelogenesis regulation of cell morphogenesis ameloblast differentiation positive regulation of enamel mineralization post-translational protein modification Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10117 13801 Ensembl ENSG00000132464 ENSMUSG00000029286 UniProt Q9NRM1 O55196 RefSeq (mRNA) NM_031889 NM_001368133 NM_017468 RefSeq (protein) NP_114095 NP_001355062 NP_059496 Location (UCSC) Chr 4: 70.63 – 70.65 Mb Chr 5: 88.64 – 88.65 Mb PubMed search
Wikidata
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Enamelin
Identifiers
Symbol	Enamelin
Pfam	PF15362
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Enamelin is an enamel matrix protein (EMPs), that in humans is encoded by the ENAM gene. It is part of the non-amelogenins, which comprise 10% of the total enamel matrix proteins. 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. 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. All other EMPs are derived from enamelin, such as amelogenin. EMPs belong to a larger family of proteins termed 'secretory calcium-binding phosphoproteins' (SCPP).

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. 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).

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.

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
• 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.

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. Point mutations can cause autosomal-dominant hypoplastic AI, and novel ENAM mutations can cause autosomal-recessive hypoplastic AI. 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.

See also

• Ameloblastin
• Amelogenin
• Amelogenesis
• Amelogenesis imperfecta

Further reading

• Gutierrez SJ, Chaves M, Torres DM, Briceño I (May 2007). "Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta". Archives of Oral Biology. 52 (5): 503–6. doi:10.1016/j.archoralbio.2006.09.014. PMID 17316551.
• Pavlic A, Petelin M, Battelino T (March 2007). "Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG". Archives of Oral Biology. 52 (3): 209–17. doi:10.1016/j.archoralbio.2006.10.010. PMID 17125728.
• Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP (November 2004). "Phosphoproteomic analysis of the developing mouse brain". Molecular & Cellular Proteomics. 3 (11): 1093–101. doi:10.1074/mcp.M400085-MCP200. PMID 15345747.
• Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, Ozdemir D, Firatli S, Aren G, Firatli E (December 2003). "Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects". Journal of Medical Genetics. 40 (12): 900–6. doi:10.1136/jmg.40.12.900. PMC 1735344. PMID 14684688.
• Hart PS, Michalec MD, Seow WK, Hart TC, Wright JT (August 2003). "Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature". Archives of Oral Biology. 48 (8): 589–96. doi:10.1016/S0003-9969(03)00114-6. PMID 12828988.
• Kida M, Ariga T, Shirakawa T, Oguchi H, Sakiyama Y (November 2002). "Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary". Journal of Dental Research. 81 (11): 738–42. doi:10.1177/154405910208101103. PMID 12407086.
• Rajpar MH, Harley K, Laing C, Davies RM, Dixon MJ (August 2001). "Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta". Human Molecular Genetics. 10 (16): 1673–7. doi:10.1093/hmg/10.16.1673. PMID 11487571.
• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Dong J, Gu TT, Simmons D, MacDougall M (October 2000). "Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus". European Journal of Oral Sciences. 108 (5): 353–8. doi:10.1034/j.1600-0722.2000.108005353.x. PMID 11037750.
• Hu CC, Hart TC, Dupont BR, Chen JJ, Sun X, Qian Q, Zhang CH, Jiang H, Mattern VL, Wright JT, Simmer JP (April 2000). "Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development". Journal of Dental Research. 79 (4): 912–9. doi:10.1177/00220345000790040501. PMID 10831092. S2CID 24476486.
• Forsman K, Lind L, Bäckman B, Westermark E, Holmgren G (September 1994). "Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q". Human Molecular Genetics. 3 (9): 1621–5. doi:10.1093/hmg/3.9.1621. PMID 7833920.

External links

• ENAM human gene location in the UCSC Genome Browser.
• ENAM human gene details in the UCSC Genome Browser.