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.

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

Institute of Microbiology of the Czech Academy of Sciences v v i 142 20 Prague 4 Czech Republic

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 Prague 128 43 Prague 2 Czech Republic

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

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

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

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$a Wald, Tomas $u Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.

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$a Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif / $c T. Wald, F. Spoutil, A. Osickova, M. Prochazkova, O. Benada, P. Kasparek, L. Bumba, OD. Klein, R. Sedlacek, P. Sebo, J. Prochazka, R. Osicka,

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$a 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.

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$a Spoutil, Frantisek $u 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.

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$a Osickova, Adriana $u 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.

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$a Prochazkova, Michaela $u 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.

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$a Benada, Oldrich $u Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.

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$a Kasparek, Petr $u 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.

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$a Bumba, Ladislav $u Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.

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$a Klein, Ophir D $u 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.

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$a Sedlacek, Radislav $u 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.

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$a Sebo, Peter $u Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.

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$a Prochazka, Jan $u 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.

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$a Osicka, Radim $u 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.

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