title: How the Pseudomonas aeruginosa ExoS toxin downregulates Rac.
abstract: Pseudomonas aeruginosa is an opportunistic bacterial pathogen. One of its major toxins, ExoS, is translocated into eukaryotic cells by a type III secretion pathway. ExoS is a dual function enzyme that affects two different Ras-related GTP binding proteins. The C-terminus inactivates Ras through ADP ribosylation, while the N-terminus inactivates Rho proteins through its GTPase activating protein (GAP) activity. Here we have determined the three-dimensional structure of a complex between Rac and the GAP domain of ExoS in the presence of GDP and AlF3. Composed of approximately 130 residues, this ExoS domain is the smallest GAP hitherto described. The GAP domain of ExoS is an all-helical protein with no obvious structural homology, and thus no recognizable evolutionary relationship, with the eukaryotic RhoGAP or RasGAP fold. Similar to other GAPs, ExoS downregulates Rac using an arginine finger to stabilize the transition state of the GTPase reaction, but the details of the ExoS-Rac interaction are unique. Considering the intrinsic resistance of P. aeruginosa to antibiotics, this might open up a new avenue towards blocking its pathogenicity.
authors.affiliation: Max-Planck-Institut für molekulare Physiologie, Abteilung Strukturelle Biologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Würtele
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.forename: K J
authors.initials: KJ
authors.lastname: Pederson
authors.forename: G
authors.initials: G
authors.lastname: Buchwald
authors.forename: M R
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: J T
authors.initials: JT
authors.lastname: Barbieri
authors.forename: A
authors.initials: A
authors.lastname: Wittinghofer
mesh_terms: D017607:Aluminum Compounds / Q000378:metabolism; D000595:Amino Acid Sequence; D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D015536:Down-Regulation; D005459:Fluorides / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry; D006153:Guanosine Diphosphate / Q000378:metabolism; D000071677:Histidine Kinase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000201:enzymology* / Q000472:pathogenicity; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017607:Aluminum Compounds; D001427:Bacterial Toxins; D020690:GTPase-Activating Proteins; C085379:rho GTPase-activating protein; D006153:Guanosine Diphosphate; D011494:Protein Kinases; D000071677:Histidine Kinase; D020744:rac GTP-Binding Proteins; D005459:Fluorides; C032311:aluminum fluoride