title: Structure of a herpesvirus-encoded cysteine protease reveals a unique class of deubiquitinating enzymes.
abstract: All members of the herpesviridae contain within their large tegument protein a cysteine protease module that displays deubiquitinating activity. We report the crystal structure of the cysteine protease domain of murine cytomegalovirus M48 (M48(USP)) in a complex with a ubiquitin (Ub)-based suicide substrate. M48(USP) adopts a papain-like fold, with the active-site cysteine forming a thioether linkage to the suicide substrate. The Ub core participates in an extensive hydrophobic interaction with an exposed beta hairpin loop of M48(USP). This Ub binding mode contributes to Ub specificity and is distinct from that observed in other deubiquitinating enzymes. Both the arrangement of active-site residues and the architecture of the interface with Ub lead us to classify this domain as the founding member of a previously unknown class of deubiquitinating enzymes.
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlieker
authors.forename: Wilhelm A
authors.initials: WA
authors.lastname: Weihofen
authors.forename: Evelyne
authors.initials: E
authors.lastname: Frijns
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kattenhorn
authors.forename: Rachelle
authors.initials: R
authors.lastname: Gaudet
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D003546:Cysteine Endopeptidases