title: Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif.
abstract: The formation of mineralized tissues is governed by extracellular matrix proteins that assemble into a 3D organic matrix directing the deposition of hydroxyapatite. Although the formation of bones and dentin depends on the self-assembly of type I collagen via the Gly-X-Y motif, the molecular mechanism by which enamel matrix proteins (EMPs) assemble into the organic matrix remains poorly understood. Here we identified a Y/F-x-x-Y/L/F-x-Y/F motif, evolutionarily conserved from the first tetrapods to man, that is crucial for higher order structure self-assembly of the key intrinsically disordered EMPs, ameloblastin and amelogenin. Using targeted mutations in mice and high-resolution imaging, we show that impairment of ameloblastin self-assembly causes disorganization of the enamel organic matrix and yields enamel with disordered hydroxyapatite crystallites. These findings define a paradigm for the molecular mechanism by which the EMPs self-assemble into supramolecular structures and demonstrate that this process is crucial for organization of the organic matrix and formation of properly structured enamel.
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Wald
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.|Czech Centre for Phenogenomics, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Spoutil
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.|Department of Biochemistry, Faculty of Science, Charles University in Prague, 128 43 Prague 2, Czech Republic.
authors.forename: Adriana
authors.initials: A
authors.lastname: Osickova
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.|Czech Centre for Phenogenomics, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Michaela
authors.identifier: 0000-0002-3773-8995
authors.initials: M
authors.lastname: Prochazkova
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Oldrich
authors.initials: O
authors.lastname: Benada
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kasparek
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Bumba
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, CA 94143.|Department of Orofacial Sciences, University of California, San Francisco, CA 94143.|Department of Pediatrics, University of California, San Francisco, CA 94143.|Institute for Human Genetics, University of California, San Francisco, CA 94143.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.|Czech Centre for Phenogenomics, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Radislav
authors.initials: R
authors.lastname: Sedlacek
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Sebo
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic; osicka@biomed.cas.cz jan.prochazka@img.cas.cz.|Czech Centre for Phenogenomics, Division of Biogenesis and Biotechnology of Natural Compounds, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Prochazka
authors.affiliation: Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic; osicka@biomed.cas.cz jan.prochazka@img.cas.cz.
authors.forename: Radim
authors.initials: R
authors.lastname: Osicka
mesh_terms: D053523:Amelogenin / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D003743:Dental Enamel / Q000378:metabolism*; D003746:Dental Enamel Proteins / Q000378:metabolism; D017886:Durapatite / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000502:physiology
chemical_list: D053523:Amelogenin; D003746:Dental Enamel Proteins; D016326:Extracellular Matrix Proteins; D064267:Intrinsically Disordered Proteins; C109069:enamel matrix proteins; D017886:Durapatite
keywords: ameloblastin; amelogenin; biomineralization; enamel; intrinsically disordered protein