title: Regulation of the sigmaE stress response by DegS: how the PDZ domain keeps the protease inactive in the resting state and allows integration of different OMP-derived stress signals upon folding stress.
abstract: The unfolded protein response of Escherichia coli is triggered by the accumulation of unassembled outer membrane proteins (OMPs) in the cellular envelope. The PDZ-protease DegS recognizes these mislocalized OMPs and initiates a proteolytic cascade that ultimately leads to the sigmaE-driven expression of a variety of factors dealing with folding stress in the periplasm and OMP assembly. The general features of how OMPs activate the protease function of DegS have not yet been systematically addressed. Furthermore, it is unknown how the PDZ domain keeps the protease inactive in the resting state, which is of crucial importance for the functioning of the entire sigmaE stress response. Here we show in atomic detail how DegS is able to integrate the information of distinct stress signals that originate from different OMPs containing a -x-Phe C-terminal motif. A dedicated loop of the protease domain, loop L3, serves as a versatile sensor for allosteric ligands. L3 is capable of interacting differently with ligands but reorients in a conserved manner to activate DegS. Our data also indicate that the PDZ domain directly inhibits protease function in the absence of stress signals by wedging loop L3 in a conformation that ultimately disrupts the proteolytic site. Thus, the PDZ domain and loop L3 of DegS define a novel molecular switch allowing strict regulation of the sigmaE stress response system.
authors.affiliation: Research Institute of Molecular Pathology-IMP, A-1030 Vienna, Austria.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hasselblatt
authors.forename: Robert
authors.initials: R
authors.lastname: Kurzbauer
authors.forename: Corinna
authors.initials: C
authors.lastname: Wilken
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.forename: Justyna
authors.initials: J
authors.lastname: Sawa
authors.forename: Juliane
authors.initials: J
authors.lastname: Kurt
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kirk
authors.forename: Sonja
authors.initials: S
authors.lastname: Hasenbein
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: Tim
authors.initials: T
authors.lastname: Clausen
mesh_terms: D000595:Amino Acid Sequence; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D012808:Sigma Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D012808:Sigma Factor; D014157:Transcription Factors; C489349:degS protein, Escherichia coli; C063202:sporulation-specific sigma factors