title: An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1.
abstract: The protein stability and chromatin functions of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) are regulated in a cell-cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of the UHRF1 PBR overlaps with the region engaging in an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-"occluded" state to a state open for multivalent histone binding. Consistently, introduction of a USP7-interaction-defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1.
authors: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors: Zhi-Min
authors: ZM
authors: Zhang
authors: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors: Scott B
authors: SB
authors: Rothbart
authors: The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
authors: David F
authors: DF
authors: Allison
authors: Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors: Qian
authors: Q
authors: Cai
authors: The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
authors: Joseph S
authors: JS
authors: Harrison
authors: Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors: Lin
authors: L
authors: Li
authors: Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors: Yinsheng
authors: Y
authors: Wang
authors: The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
authors: Brian D
authors: BD
authors: Strahl
authors: The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
authors: Gang Greg
authors: GG
authors: Wang
authors: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA. Electronic address: jikui.song@ucr.edu.
authors: Jikui
authors: J
authors: Song
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002843:Chromatin; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7