Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate

Kathy A. Gelato, Maria Tauber, Michelle S. Ong, Stefan Winter, Kyoko Hiragami-Hamada, Julia Sindlinger, Alexander Lemak, Yvette Bultsma, Scott Houliston, Dirk Schwarzer, Nullin Divecha, Cheryl H. Arrowsmith, Wolfgang Fischle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

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 anessential 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.

Original languageEnglish (US)
Pages (from-to)905-919
Number of pages15
JournalMolecular cell
Volume54
Issue number6
DOIs
StatePublished - Jun 19 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank members of the Fischle lab for invaluable comments and discussions. Katharina Rehn helped with peptide synthesis, Nadin Zimmermann with MS analysis of peptides, and Sven Johannsson with quantitative analysis of cellular phenotypes. We are thankful to Thomas Conrad for fermenter cell culture and Christer Ejsing (University of Southern Denmark) for PIP MS work. K.A.G. was supported by an EMBO long-term fellowship; K.H.-H. is supported by a Marie Curie Fellowship (IEF, FP7). This work was funded by the Max Planck Society (W.F.), the German Research Foundation (DFG grants FI 1513/2-1 to W.F. and SCHW 1163/3-1 to D.S.), Cancer Research UK (N.D.), and the Natural Sciences and Engineering Research Council of Canada (grant 372475-10 to C.H.A.). C.H.A. holds a Canada Research Chair in Structural Genomics. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada through the Ontario Genomics Institute [OGI-055], GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry Research and Innovation, Pfizer, Takeda, and the Wellcome Trust (092809/Z/10/Z).

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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