ID   ENAM_HUMAN              Reviewed;        1142 AA.
AC   Q9NRM1; Q17RI5; Q9H3D1;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   04-NOV-2008, sequence version 3.
DT   24-JAN-2024, entry version 167.
DE   RecName: Full=Enamelin;
DE   Flags: Precursor;
GN   Name=ENAM;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-648 AND GLN-763.
RX   PubMed=18245370; DOI=10.1534/genetics.107.077123;
RA   Kelley J.L., Swanson W.J.;
RT   "Dietary change and adaptive evolution of enamelin in humans and among
RT   primates.";
RL   Genetics 178:1595-1603(2008).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Hu C.-C., Qian Q., Zhang C., Fukae M., Uchida T., Simmer J.P.;
RT   "cDNA sequence of human enamelin.";
RL   Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 1014-1142.
RX   PubMed=11037750; DOI=10.1034/j.1600-0722.2000.108005353.x;
RA   Dong J., Gu T.T., Simmons D., MacDougall M.;
RT   "Enamelin maps to human chromosome 4q21 within the autosomal dominant
RT   amelogenesis imperfecta locus.";
RL   Eur. J. Oral Sci. 108:353-358(2000).
RN   [6]
RP   INVOLVEMENT IN AI1B, AND TISSUE SPECIFICITY.
RX   PubMed=11487571; DOI=10.1093/hmg/10.16.1673;
RA   Rajpar M.H., Harley K., Laing C., Davies R.M., Dixon M.J.;
RT   "Mutation of the gene encoding the enamel-specific protein, enamelin,
RT   causes autosomal-dominant amelogenesis imperfecta.";
RL   Hum. Mol. Genet. 10:1673-1677(2001).
RN   [7]
RP   INVOLVEMENT IN AI1B.
RX   PubMed=11978766; DOI=10.1093/hmg/11.9.1069;
RA   Mardh C.K., Backman B., Holmgren G., Hu J.C., Simmer J.P., Forsman-Semb K.;
RT   "A nonsense mutation in the enamelin gene causes local hypoplastic
RT   autosomal dominant amelogenesis imperfecta (AIH2).";
RL   Hum. Mol. Genet. 11:1069-1074(2002).
RN   [8]
RP   INVOLVEMENT IN AI1C.
RX   PubMed=14684688; DOI=10.1136/jmg.40.12.900;
RA   Hart T.C., Hart P.S., Gorry M.C., Michalec M.D., Ryu O.H., Uygur C.,
RA   Ozdemir D., Firatli S., Aren G., Firatli E.;
RT   "Novel ENAM mutation responsible for autosomal recessive amelogenesis
RT   imperfecta and localised enamel defects.";
RL   J. Med. Genet. 40:900-906(2003).
RN   [9]
RP   PHOSPHORYLATION AT SER-191 AND SER-216, VARIANT AI1B LEU-216, VARIANT AI1C
RP   LEU-216, CHARACTERIZATION OF VARIANT AI1B LEU-216, CHARACTERIZATION OF
RP   VARIANT AI1C LEU-216, AND MUTAGENESIS OF SER-191.
RX   PubMed=25789606; DOI=10.7554/elife.06120;
RA   Cui J., Xiao J., Tagliabracci V.S., Wen J., Rahdar M., Dixon J.E.;
RT   "A secretory kinase complex regulates extracellular protein
RT   phosphorylation.";
RL   Elife 4:0-0(2015).
RN   [10]
RP   VARIANT AI1B LEU-216, AND VARIANT AI1C LEU-216.
RX   PubMed=20439930; DOI=10.1177/0022034510365662;
RA   Chan H.C., Mai L., Oikonomopoulou A., Chan H.L., Richardson A.S.,
RA   Wang S.K., Simmer J.P., Hu J.C.;
RT   "Altered enamelin phosphorylation site causes amelogenesis imperfecta.";
RL   J. Dent. Res. 89:695-699(2010).
CC   -!- FUNCTION: Involved in the mineralization and structural organization of
CC       enamel. Involved in the extension of enamel during the secretory stage
CC       of dental enamel formation. {ECO:0000250|UniProtKB:O97939}.
CC   -!- INTERACTION:
CC       Q9NRM1; Q8IXL6: FAM20C; NbExp=2; IntAct=EBI-11892601, EBI-7147442;
CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC       matrix {ECO:0000250|UniProtKB:O97939}.
CC   -!- TISSUE SPECIFICITY: Expressed in tooth particularly in odontoblast,
CC       ameloblast and cementoblast. {ECO:0000269|PubMed:11487571}.
CC   -!- PTM: Phosphorylated by FAM20C in vitro. {ECO:0000269|PubMed:25789606}.
CC   -!- DISEASE: Amelogenesis imperfecta 1B (AI1B) [MIM:104500]: An autosomal
CC       dominant defect of enamel formation. Clinical manifestations may be
CC       variable. Some cases present with generalized enamel hypoplasia
CC       resulting in small, smooth, yellow and widely spaced teeth (smooth
CC       hypoplastic AI). Others show horizontal rows of pits, grooves or a
CC       hypoplastic area in the enamel (local hypoplastic AI).
CC       {ECO:0000269|PubMed:11487571, ECO:0000269|PubMed:11978766,
CC       ECO:0000269|PubMed:20439930, ECO:0000269|PubMed:25789606}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Amelogenesis imperfecta 1C (AI1C) [MIM:204650]: An autosomal
CC       recessive defect of dental enamel formation. Teeth show local
CC       hypoplastic and unmineralized enamel, and a yellow-brown discoloration.
CC       Enamel defects can be associated with facial and oral features
CC       including vertical dysgnathia and anterior openbite malocclusion.
CC       {ECO:0000269|PubMed:14684688, ECO:0000269|PubMed:20439930,
CC       ECO:0000269|PubMed:25789606}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
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DR   EMBL; EU482096; ACA43029.1; -; Genomic_DNA.
DR   EMBL; AF125373; AAG43242.1; -; mRNA.
DR   EMBL; CH471057; EAX05625.1; -; Genomic_DNA.
DR   EMBL; BC117308; AAI17309.1; -; mRNA.
DR   EMBL; BC117310; AAI17311.1; -; mRNA.
DR   EMBL; AF210247; AAF73847.1; -; mRNA.
DR   CCDS; CCDS3544.2; -.
DR   RefSeq; NP_114095.2; NM_031889.2.
DR   RefSeq; XP_006714119.1; XM_006714056.3.
DR   AlphaFoldDB; Q9NRM1; -.
DR   BioGRID; 115422; 3.
DR   IntAct; Q9NRM1; 4.
DR   MINT; Q9NRM1; -.
DR   STRING; 9606.ENSP00000379383; -.
DR   GlyCosmos; Q9NRM1; 10 sites, No reported glycans.
DR   GlyGen; Q9NRM1; 10 sites.
DR   iPTMnet; Q9NRM1; -.
DR   PhosphoSitePlus; Q9NRM1; -.
DR   BioMuta; ENAM; -.
DR   DMDM; 212276506; -.
DR   EPD; Q9NRM1; -.
DR   MassIVE; Q9NRM1; -.
DR   PaxDb; 9606-ENSP00000379383; -.
DR   PeptideAtlas; Q9NRM1; -.
DR   Antibodypedia; 24350; 82 antibodies from 15 providers.
DR   DNASU; 10117; -.
DR   Ensembl; ENST00000396073.4; ENSP00000379383.4; ENSG00000132464.13.
DR   GeneID; 10117; -.
DR   KEGG; hsa:10117; -.
DR   MANE-Select; ENST00000396073.4; ENSP00000379383.4; NM_031889.3; NP_114095.2.
DR   UCSC; uc011caw.2; human.
DR   AGR; HGNC:3344; -.
DR   CTD; 10117; -.
DR   DisGeNET; 10117; -.
DR   GeneCards; ENAM; -.
DR   HGNC; HGNC:3344; ENAM.
DR   HPA; ENSG00000132464; Tissue enhanced (epididymis, heart muscle, kidney, skeletal muscle).
DR   MalaCards; ENAM; -.
DR   MIM; 104500; phenotype.
DR   MIM; 204650; phenotype.
DR   MIM; 606585; gene.
DR   neXtProt; NX_Q9NRM1; -.
DR   OpenTargets; ENSG00000132464; -.
DR   Orphanet; 100031; Hypoplastic amelogenesis imperfecta.
DR   PharmGKB; PA27781; -.
DR   VEuPathDB; HostDB:ENSG00000132464; -.
DR   eggNOG; ENOG502R69E; Eukaryota.
DR   GeneTree; ENSGT00440000037826; -.
DR   HOGENOM; CLU_280412_0_0_1; -.
DR   InParanoid; Q9NRM1; -.
DR   OMA; WNSWDHR; -.
DR   OrthoDB; 5322090at2759; -.
DR   PhylomeDB; Q9NRM1; -.
DR   TreeFam; TF337278; -.
DR   PathwayCommons; Q9NRM1; -.
DR   Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR   SignaLink; Q9NRM1; -.
DR   BioGRID-ORCS; 10117; 9 hits in 1142 CRISPR screens.
DR   GeneWiki; ENAM; -.
DR   GenomeRNAi; 10117; -.
DR   Pharos; Q9NRM1; Tbio.
DR   PRO; PR:Q9NRM1; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; Q9NRM1; Protein.
DR   Bgee; ENSG00000132464; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 70 other cell types or tissues.
DR   ExpressionAtlas; Q9NRM1; baseline and differential.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR   GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-KW.
DR   GO; GO:0030345; F:structural constituent of tooth enamel; IBA:GO_Central.
DR   GO; GO:0036305; P:ameloblast differentiation; IBA:GO_Central.
DR   GO; GO:0097186; P:amelogenesis; IBA:GO_Central.
DR   GO; GO:0031214; P:biomineral tissue development; IEA:UniProtKB-KW.
DR   GO; GO:0070175; P:positive regulation of enamel mineralization; IBA:GO_Central.
DR   InterPro; IPR015673; Enamelin.
DR   PANTHER; PTHR16784; ENAMELIN; 1.
DR   PANTHER; PTHR16784:SF2; ENAMELIN; 1.
DR   Pfam; PF15362; Enamelin; 1.
DR   Genevisible; Q9NRM1; HS.
PE   1: Evidence at protein level;
KW   Amelogenesis imperfecta; Biomineralization; Disease variant;
KW   Extracellular matrix; Glycoprotein; Phosphoprotein; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..39
FT                   /evidence="ECO:0000255"
FT   CHAIN           40..1142
FT                   /note="Enamelin"
FT                   /id="PRO_0000021174"
FT   REGION          88..193
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          214..326
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          398..671
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          874..955
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1020..1048
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1062..1092
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        90..104
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        120..152
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        174..188
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        218..236
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        239..286
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        299..320
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        449..470
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        504..519
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        528..542
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        571..591
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        897..938
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1028..1048
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1063..1092
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         191
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:25789606"
FT   MOD_RES         216
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:25789606"
FT   CARBOHYD        114
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        126
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        245
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        252
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        265
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        296
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        467
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        534
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        934
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        1040
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         216
FT                   /note="S -> L (in AI1B and AI1C; decreased phosphorylation
FT                   by FAM20C; dbSNP:rs867263935)"
FT                   /evidence="ECO:0000269|PubMed:20439930,
FT                   ECO:0000305|PubMed:25789606"
FT                   /id="VAR_073665"
FT   VARIANT         576
FT                   /note="F -> L (in dbSNP:rs2609428)"
FT                   /id="VAR_024311"
FT   VARIANT         648
FT                   /note="I -> T (in dbSNP:rs7671281)"
FT                   /evidence="ECO:0000269|PubMed:18245370"
FT                   /id="VAR_024312"
FT   VARIANT         724
FT                   /note="P -> L (in dbSNP:rs3796703)"
FT                   /id="VAR_020105"
FT   VARIANT         763
FT                   /note="R -> Q (in dbSNP:rs3796704)"
FT                   /evidence="ECO:0000269|PubMed:18245370"
FT                   /id="VAR_024313"
FT   VARIANT         767
FT                   /note="D -> G (in dbSNP:rs3796705)"
FT                   /id="VAR_047076"
FT   MUTAGEN         191
FT                   /note="S->A: Decreased phosphorylation by FAM20C."
FT                   /evidence="ECO:0000269|PubMed:25789606"
FT   CONFLICT        284
FT                   /note="P -> S (in Ref. 2; AAG43242)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        286
FT                   /note="Q -> R (in Ref. 2; AAG43242)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        948
FT                   /note="D -> G (in Ref. 2; AAG43242)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1142 AA;  128785 MW;  28274A71BE947EB1 CRC64;
     MLVLRCRLGT SFPKLDNLVP KGKMKILLVF LGLLGNSVAM PMHMPRMPGF SSKSEEMMRY
     NQFNFMNGPH MAHLGPFFGN GLPQQFPQYQ MPMWPQPPPN TWHPRKSSAP KRHNKTDQTQ
     ETQKPNQTQS KKPPQKRPLK QPSHNQPQPE EEAQPPQAFP PFGNGLFPYQ QPPWQIPQRL
     PPPGYGRPPI SNEEGGNPYF GYFGYHGFGG RPPYYSEEMF EQDFEKPKEE DPPKAESPGT
     EPTANSTVTE TNSTQPNPKG SQGGNDTSPT GNSTPGLNTG NNPPAQNGIG PLPAVNASGQ
     GGPGSQIPWR PSQPNIRENH PYPNIRNFPS GRQWYFTGTV MGHRQNRPFY RNQQVQRGPR
     WNFFAWERKQ VARPGNPVYH KAYPPTSRGN YPNYAGNPAN LRRKPQGPNK HPVGTTVAPL
     GPKPGPVVRN EKIQNPKEKP LGPKEQIIVP TKNPTSPWRN SQQYEVNKSN YKLPHSEGYM
     PVPNFNSVDQ HENSYYPRGD SRKVPNSDGQ TQSQNLPKGI VLGSRRMPYE SETNQSELKH
     SSYQPAVYPE EIPSPAKEHF PAGRNTWDHQ EISPPFKEDP GRQEEHLPHP SHGSRGSVFY
     PEYNPYDPRE NSPYLRGNTW DERDDSPNTM GQKESPLYPI NTPDQKEIVP YNEEDPVDPT
     GDEVFPGQNR WGEELSFKGG PTVRHYEGEQ YTSNQPKEYL PYSLDNPSKP REDFYYSEFY
     PWSPDENFPS YNTASTMPPP IESRGYYVNN AAGPEESTLF PSRNSWDHRI QAQGQRERRP
     YFNRNIWDQA THLQKAPARP PDQKGNQPYY SNTPAGLQKN PIWHEGENLN YGMQITRMNS
     PEREHSSFPN FIPPSYPSGQ KEAHLFHLSQ RGSCCAGSST GPKDNPLALQ DYTPSYGLAP
     GENQDTSPLY TDGSHTKQTR DIISPTSILP GQRNSSEKRE SQNPFRDDVS TLRRNTPCSI
     KNQLGQKEIM PFPEASSLQS KNTPCLKNDL GGDGNNILEQ VFEDNQLNER TVDLTPEQLV
     IGTPDEGSNP EGIQSQVQEN ESERQQQRPS NILHLPCFGS KLAKHHSSTT GTPSSDGRQS
     PFDGDSITPT ENPNTLVELA TEEQFKSINV DPLDADEHSP FEFLQRGTNV QDQVQDCLLL
     QA
//