6P5L

Crystal Structure of Ubl123 with an EZH2 peptide

Summary for 6P5L

• Entry DOI: 10.2210/pdb6p5l/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 7, PRO-ARG-LYS-LYS-LYS-ARG-LYS-HIS (2 entities in total)
• Functional Keywords: complex deubiquitinase, nuclear protein, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 84384.74

Authors

Saridakis, V. (deposition date: 2019-05-30, release date: 2020-05-06, Last modification date: 2023-10-11)

Primary citation

Gagarina, V.,Bojagora, A.,Lacdao, I.K.,Luthra, N.,Pfoh, R.,Mohseni, S.,Chaharlangi, D.,Tan, N.,Saridakis, V.
Structural Basis of the Interaction Between Ubiquitin Specific Protease 7 and Enhancer of Zeste Homolog 2.
J.Mol.Biol., 432:897-912, 2020

PubMed Abstract: USP7 is a deubiquitinase that regulates many diverse cellular processes, including tumor suppression, epigenetics, and genome stability. Several substrates, including GMPS, UHRF1, and ICP0, were shown to bear a specific KxxxK motif that interacts within the C-terminal region of USP7. We identified a similar motif in Enhancer of Zeste 2 (EZH2), the histone methyltransferase found within Polycomb Repressive Complex 2 (PRC2). PRC2 is responsible for the methylation of Histone 3 Lys27 (H3K27) leading to gene silencing. GST pull-down and coimmunoprecipitation experiments showed that USP7 interacts with EZH2. We determined the structural basis of interaction between USP7 and EZH2 and identified residues mediating the interaction. Mutations in these critical residues disrupted the interaction between USP7 and EZH2. Furthermore, USP7 silencing and knockout experiments showed decreased EZH2 levels in HCT116 carcinoma cells. Finally, we demonstrated decreased H3K27Me3 levels in HCT116 USP7 knockout cells. These results indicate that USP7 interacts with EZH2 and regulates both its stability and function.

PubMed: 31866294
DOI: 10.1016/j.jmb.2019.12.026

Experimental method

X-RAY DIFFRACTION (3.296 Å)