Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9
PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex w...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713004762 |
| _version_ | 1818563403070832640 |
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| author | Hong Wu Nikolas Mathioudakis Boubou Diagouraga Aiping Dong Ludmila Dombrovski Frédéric Baudat Stephen Cusack Bernard de Massy Jan Kadlec |
| author_facet | Hong Wu Nikolas Mathioudakis Boubou Diagouraga Aiping Dong Ludmila Dombrovski Frédéric Baudat Stephen Cusack Bernard de Massy Jan Kadlec |
| author_sort | Hong Wu |
| collection | DOAJ |
| description | PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity. |
| first_indexed | 2024-12-14T01:16:09Z |
| format | Article |
| id | doaj.art-441a5c8c07ee4339885fc3874938ebc6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T01:16:09Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-441a5c8c07ee4339885fc3874938ebc62022-12-21T23:22:34ZengElsevierCell Reports2211-12472013-10-0151132010.1016/j.celrep.2013.08.035Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9Hong Wu0Nikolas Mathioudakis1Boubou Diagouraga2Aiping Dong3Ludmila Dombrovski4Frédéric Baudat5Stephen Cusack6Bernard de Massy7Jan Kadlec8Structural Genomics Consortium, University of Toronto, MaRS Center, South Tower, 7th Floor, 101 College Street, Toronto, ON M5G 1L7, CanadaEuropean Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, FranceInstitute of Human Genetics, UPR 1142, CNRS, 141 rue de la Cardonille, 34396 Montpellier, FranceStructural Genomics Consortium, University of Toronto, MaRS Center, South Tower, 7th Floor, 101 College Street, Toronto, ON M5G 1L7, CanadaStructural Genomics Consortium, University of Toronto, MaRS Center, South Tower, 7th Floor, 101 College Street, Toronto, ON M5G 1L7, CanadaInstitute of Human Genetics, UPR 1142, CNRS, 141 rue de la Cardonille, 34396 Montpellier, FranceEuropean Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, FranceInstitute of Human Genetics, UPR 1142, CNRS, 141 rue de la Cardonille, 34396 Montpellier, FranceEuropean Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, FrancePRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity.http://www.sciencedirect.com/science/article/pii/S2211124713004762 |
| spellingShingle | Hong Wu Nikolas Mathioudakis Boubou Diagouraga Aiping Dong Ludmila Dombrovski Frédéric Baudat Stephen Cusack Bernard de Massy Jan Kadlec Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 Cell Reports |
| title | Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 |
| title_full | Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 |
| title_fullStr | Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 |
| title_full_unstemmed | Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 |
| title_short | Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 |
| title_sort | molecular basis for the regulation of the h3k4 methyltransferase activity of prdm9 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713004762 |
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