title: Chemical biology approaches reveal conserved features of a C-terminal processing PDZ protease.
abstract: Several proteases like the high temperature requirement A (HtrA) protein family containing internal or C-terminal PDZ domains play key roles in protein quality control in the cell envelope of Gram-negative bacteria. While several HtrA proteases have been extensively characterized, many features of C-terminal processing proteases such as tail-specific protease (Tsp) are still unknown. To fully understand these cellular control systems, individual domains need to be targeted by specific peptides acting as activators or inhibitors. Here, we describe the identification and design of potent inhibitors and activators of Tsp. Suitable synthetic substrates of Tsp were identified and served as a basis for the generation of boronic acid-based peptide inhibitors. In addition, a proteomic screen of E. coli cell envelope proteins using a synthetic peptide library was performed to identify peptides capable of amplifying Tsp's proteolytic activity. The implications of these findings for the regulation of PDZ proteases and for future mechanistic studies are discussed.
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitätsstrasse 2, 45117 Essen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Weski
authors.forename: Michael
authors.initials: M
authors.lastname: Meltzer
authors.forename: Lina
authors.initials: L
authors.lastname: Spaan
authors.forename: Timon
authors.initials: T
authors.lastname: Mönig
authors.forename: Julian
authors.initials: J
authors.lastname: Oeljeklaus
authors.forename: Patrick
authors.initials: P
authors.lastname: Hauske
authors.forename: Lars
authors.initials: L
authors.lastname: Vouilleme
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.forename: Prisca
authors.initials: P
authors.lastname: Boisguerin
authors.forename: Dana
authors.initials: D
authors.lastname: Boyd
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
mesh_terms: D001897:Boronic Acids / Q000737:chemistry; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D015394:Molecular Structure; D054731:PDZ Domains; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001897:Boronic Acids; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011480:Protease Inhibitors; D010450:Endopeptidases; C072135:C-terminal processing peptidase