title: Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes.
abstract: Deubiquitinating enzymes (DUBs) are responsible for reversing mono- and polyubiquitination of proteins and play essential roles in numerous cellular processes. Close to 100 human DUBs have been identified and are classified into five families, with the ubiquitin-specific protease (USP) family being the largest (>50 members). The binding of ubiquitin (Ub) to USP is strikingly different from that observed for the DUBs in the ubiquitin C-terminal hydrolase (UCH) and ovarian tumor domain protease (OTU) families. We generated a panel of mutant ubiquitins and used them to probe the ubiquitin's interaction with a number of USPs. Our results revealed a remarkable divergence of USP-Ub interactions among the USP catalytic domains. Our double-mutant cycle analysis targeting the ubiquitin residues located in the tip, the central body, and the tail of ubiquitin also demonstrated different crosstalk among the USP-Ub interactions. This work uncovered intriguing divergence in the ubiquitin-binding mode in the USP family DUBs and raised the possibility of targeting the ubiquitin-binding hot spots on USPs for selective inhibition of USPs by small molecule antagonists.
authors: Department of Chemistry and Biochemistry, University of Delaware, 214A Drake Hall, Newark, Delaware 19716, United States.
authors: Adam H
authors: AH
authors: Tencer
authors: Department of Chemistry and Biochemistry, University of Delaware, 214A Drake Hall, Newark, Delaware 19716, United States.
authors: Qin
authors: Q
authors: Liang
authors: Department of Chemistry and Biochemistry, University of Delaware, 214A Drake Hall, Newark, Delaware 19716, United States.
authors: Zhihao
authors: Z
authors: Zhuang
mesh_terms: D002384:Catalysis; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000235:genetics; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D025801:Ubiquitin; D010447:Peptide Hydrolases