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An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1 Zhi-Min Zhang University of California, Riverside

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An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1 Zhi-Min Zhang University of California, Riverside University of the Pacific Scholarly Commons College of the Pacific aF culty Articles All Faculty Scholarship 9-1-2015 An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1 Zhi-Min Zhang University of California, Riverside Scott .B Rothbart Van Andel Research Institute David F. Allison University of North Carolina at Chapel Hill Qian Cai University of California, Riverside Joseph S. Harrison University of the Pacific, [email protected] See next page for additional authors Follow this and additional works at: https://scholarlycommons.pacific.edu/cop-facarticles Part of the Biochemistry, Biophysics, and Structural Biology Commons, and the Chemistry Commons Recommended Citation Zhang, Z., Rothbart, S. B., Allison, D. F., Cai, Q., Harrison, J. S., Li, L., Wang, Y., Strahl, B. D., Wang, G. G., & Song, J. (2015). An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1. Cell Reports, 12(9), 1400–1406. DOI: 10.1016/j.celrep.2015.07.046 https://scholarlycommons.pacific.edu/cop-facarticles/575 This Article is brought to you for free and open access by the All Faculty Scholarship at Scholarly Commons. It has been accepted for inclusion in College of the Pacific aF culty Articles by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. Authors Zhi-Min Zhang, Scott .B Rothbart, David F. Allison, Qian Cai, Joseph S. Harrison, Lin Li, Yinsheng Wang, Brian D. Strahl, Gang Greg Wang, and Jikui Song This article is available at Scholarly Commons: https://scholarlycommons.pacific.edu/cop-facarticles/575 Report An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1 Graphical Abstract Authors Zhi-Min Zhang, Scott B. Rothbart, David F. Allison, ..., Brian D. Strahl, Gang Greg Wang, Jikui Song Correspondence [email protected] In Brief Zhang et al. report the crystal structure of USP7 ubiquitin-like domains in complex with the UHRF1 polybasic region. Structural analysis, combined with biochemical and cellular analysis, reveals that the USP7 interaction influences both ubiquitination and chromatin association of UHRF1. Highlights Accession Numbers d USP7 ubiquitin-like domains bind to the UHRF1 polybasic 5C6D region d USP7 interaction promotes USP7-mediated deubiquitination of UHRF1 d USP7 allosterically regulates the conformational states of UHRF1 d USP7 interaction affects the chromatin association of UHRF1 Zhang et al., 2015, Cell Reports 12, 1400–1406 September 1, 2015 ª2015 The Authors http://dx.doi.org/10.1016/j.celrep.2015.07.046 Cell Reports Report An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1 Zhi-Min Zhang,1 Scott B. Rothbart,2 David F. Allison,3 Qian Cai,4 Joseph S. Harrison,3,5 Lin Li,4 Yinsheng Wang,4 Brian D. Strahl,3,5 Gang Greg Wang,3,5 and Jikui Song1,* 1Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA 2Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA 3The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA 4Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA 5Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.celrep.2015.07.046 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). SUMMARY multidomain protein that plays critical roles in regulating various processes, such as DNMT1 (DNA methyltransferase 1)-medi- The protein stability and chromatin functions of ated DNA methylation maintenance (Bostick et al., 2007; Sharif UHRF1 (ubiquitin-like, containing PHD and RING et al., 2007). UHRF1 contains a ubiquitin-like (UBL) domain at finger domains, 1) are regulated in a cell-cycle-depen- the N terminus, followed by a tandem Tudor domain (TTD), a dent manner. We report a structural characterization plant homeodomain (PHD), a SET- and RING-associated (SRA) of the complex between UHRF1 and the deubiquiti- domain, and a RING domain (Figure 1A). Among these protein nase USP7. The first two UBL domains of USP7 bind modules, the PHD and TTD recognize the N-terminal tail of his- tone H3 unmethylated at arginine 2 (Hu et al., 2011; Lallous to the polybasic region (PBR) of UHRF1, and this in- et al., 2011; Rajakumara et al., 2011) and dimethylated/trimethy- teraction is required for the USP7-mediated deubiqui- lated at lysine 9 (H3K9me2/3) (Arita et al., 2012; Cheng et al., tination of UHRF1. Importantly, we find that the USP7- 2013; Karagianni et al., 2008; Rothbart et al., 2012, 2013; Xie binding site of the UHRF1 PBR overlaps with the et al., 2012), respectively, whereas the SRA domain specifically region engaging in an intramolecular interaction with binds to hemimethylated CpG sites (Arita et al., 2008; Avvaku- the N-terminal tandem Tudor domain (TTD). We mov et al., 2008; Bostick et al., 2007; Hashimoto et al., 2008; show that the USP7-UHRF1 interaction perturbs the Sharif et al., 2007). The RING domain of UHRF1 has been shown TTD-PBR interaction of UHRF1, thereby shifting the to serve as an E3 ubiquitin ligase to promote monoubiquitination conformation of UHRF1 from a TTD-‘‘occluded’’ state of H3 at lysine 18 and/or 23 (Nishiyama et al., 2013; Qin et al., to a state open for multivalent histone binding. Con- 2015), which in turn recruits DNMT1 to replicating chromatin. sistently, introduction of a USP7-interaction-defec- Despite these advances, the mechanism underlying the re- gulation of UHRF1 remains to be elucidated. Indeed, emerging tive mutation to UHRF1 significantly reduces its chro- evidence has shown that UHRF1 is subject to temporal and matin association. Together, these results link USP7 spatial control (Gelato et al., 2014; Ma et al., 2012). First, the interaction to the dynamic deubiquitination and chro- stability of UHRF1 is regulated by ubiquitination in a cell-cycle- matin association of UHRF1. dependent manner (Ma et al., 2012). During S phase, deubiquiti- nase USP7 (ubiquitin-specific-processing protease 7) associates INTRODUCTION with UHRF1, keeping it from being ubiquitinated (Ma et al., 2012). When cells enter mitosis, USP7 dissociates from UHRF1, One of the fundamental principles in epigenetic regulation in- exposing it for ubiquitination and consequent proteasomal volves temporal and spatial control of macromolecular machin- degradation (Ma et al., 2012). Second, the chromatin association eries that govern epigenetic events. Epigenetic modifications, of UHRF1 peaks in mid S phase to accompany pericentromeric including DNA methylation and histone modifications, are recog- heterochromatin replication (Miura et al., 2001; Papait et al., nized by a diverse family of effector proteins (Bogdanovic and 2007; Taylor et al., 2013), which is likely mediated by a conforma- Veenstra, 2009; Musselman et al., 2012) whose functions are tional transition between two alternative functional states of often subject to dynamic regulation in response to environmental UHRF1 (Gelato et al., 2014). In one state, the H3K9me3-binding cues. However, how these chromatin effector proteins are regu- site of the UHRF1 TTD is occluded due to its intramolecular inter- lated remains incompletely understood. action with a C-terminal polybasic region (PBR). In the second UHRF1 (ubiquitin-like, containing PHD and RING finger do- state, the TTD is relieved from the PBR interaction and thus forms mains, 1), also known as ICBP90 and NP95 in mouse, is a a multivalent histone-binding cassette with the PHD (Gelato et al., 1400 Cell Reports 12, 1400–1406, September 1, 2015 ª2015 The Authors Figure 1. Identification of the UHRF1 and USP7 Interaction Domains (A) Domain architectures of UHRF1 and USP7. The UHRF1 fragments used for biochemical analysis are labeled with residue numbers. TRAF, tumor necrosis factor receptor-associated factor. (B and C) ITC binding curves for USP7 UBL1-2 over UHRF1SRA-RING (B) and UHRF1647–678 (C). See also Figure S1. gion between the SRA and RING finger domains of UHRF1 (residues 600–687; UHRF1600–687)(Figure 1A) (Ma et al., 2012). To further map the USP7 and UHRF1 interaction interface, we per- formed isothermal titration calorimetry (ITC) to measure the binding between truncated USP7 and UHRF1 fragments. The first two UBL domains (UBL1-2) of USP7 interact directly with a fragment of UHRF1 encompassing its SRA and RING domains (residues 419–806; UHRF1SRA-RING), with a dissociation con- stant (Kd) of 1.30 mM(Figure 1B). To nar- row this interaction surface further, we showed that the UBL1-2 dual domain of USP7 binds to UHRF1600–687 with a Kd of 1.42 mM(Figure S1A), and comparable binding activity is observed (Kd 1.52 mM) when we truncated UHRF1 further to a 32-amino acid sequence, UHRF1647–678 (Figure 1B). By contrast, we did not 2014). Binding of the signaling molecule phosphatidylinositol observe appreciable interaction between the first UBL domain 5-phosphate (PI5P) to the UHRF1 PBR switches the UHRF1 (UBL1) of USP7 and UHRF1SRA-RING (Figure S1B), indicating that conformation from the TTD-‘‘occluded’’ state to the TTD-PHD UBL1 alone is insufficient for mediating the UHRF1-USP7 inter- multivalent state, which leads to its increased heterochromatin action. Collectively, these data show that the UHRF1647–678 frag- association (Gelato et al., 2014). However, how networks of inter- ment and the USP7 UBL1-2 domains mediate the UHRF1-USP7 actions functionally regulate UHRF1 in cells remains unresolved. interaction. In this study, we characterized the interaction between UHRF1 and USP7 by structure determination of the UHRF1-USP7 com- Structure of the UHRF1647–678-USP7 UBL1–3 Complex plex. Our structural analyses reveal that the UHRF1-USP7 inter- Next, to provide the molecular basis for the UHRF1-USP7 inter- action is mediated by the first two UBL domains of USP7 and the action, we determined the crystal structure of UHRF1647–678 in PBR of UHRF1.
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