title: Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate.
abstract: UHRF1 is a multidomain protein crucially linking histone H3 modification states and DNA methylation. While the interaction properties of its specific domains are well characterized, little is known about the regulation of these functionalities. We show that UHRF1 exists in distinct active states, binding either unmodified H3 or the H3 lysine 9 trimethylation (H3K9me3) modification. A polybasic region (PBR) in the C terminus blocks interaction of a tandem tudor domain (TTD) with H3K9me3 by occupying an essential peptide-binding groove. In this state the plant homeodomain (PHD) mediates interaction with the extreme N terminus of the unmodified H3 tail. Binding of the phosphatidylinositol phosphate PI5P to the PBR of UHRF1 results in a conformational rearrangement of the domains, allowing the TTD to bind H3K9me3. Our results define an allosteric mechanism controlling heterochromatin association of an essential regulatory protein of epigenetic states and identify a functional role for enigmatic nuclear phosphatidylinositol phosphates.
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Gelato
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Tauber
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ong
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hiragami-Hamada
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Sindlinger
authors.affiliation: Princess Margaret Cancer Center, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lemak
authors.affiliation: Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Bultsma
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Center, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Houliston
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schwarzer
authors.affiliation: Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Center, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Electronic address: wfischl@gwdg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischle
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D006367:HeLa Cells; D006570:Heterochromatin / Q000502:physiology; D006657:Histones / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases