Journal
STRUCTURE
Volume 26, Issue 2, Pages 304-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.12.016
Keywords
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Funding
- Kimmel Scholar Awards from Sidney Kimmel Foundation for Cancer Research
- March of Dimes Foundation [1-FY15-345]
- NIH [1R35GM119721]
- NIH
- National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R35GM119721] Funding Source: NIH RePORTER
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UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) is one of the essential components of mammalian DNA methylation machinery. Chromatin association of UHRF1 is controlled via an interplay between its intramolecular interaction and dual recognition of histone H3 trimethylated at lysine 9 (H3K9me3) and hemimethylated DNA. Here, we report the crystal structure of the N-terminal tandem Tudor domain (TTD) of UHRF1 in complex with the C-terminal polybasic region (PBR). Structural analysis reveals that PBR binding leads to displacement of the TTD-plant homeodomain (PHD) linker, as well as blockage of the H3K9me3-engaging cage, both of which contribute to a chromatin-occluded UHRF1 conformation. Disruption of the TTD-PBR interaction, which is facilitated by the binding of UHRF1 to hemimethylated DNA or regulatory protein USP7, shifts the UHRF1 conformation toward an open state, allowing for efficient H3K9me3 binding. Together, this study provides structural basis for the allosteric regulation of UHRF1.
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