Modulation of host signaling by a bacterial mimic: structure of the Salmonella effector SptP bound to Rac1.
Salmonella spp. utilize a specialized protein secretion system to deliver a battery of effector proteins into host cells. Several of these effectors stimulate Cdc42- and Rac1-dependent cytoskeletal changes that promote bacterial internalization. These potentially cytotoxic alterations are rapidly reversed by the effector SptP, a tyrosine phosphatase and GTPase activating protein (GAP) that targets Cdc42 and Rac1. The 2.3 A resolution crystal structure of an SptP-Rac1 transition state complex reveals an unusual GAP architecture that mimics host functional homologs. The phosphatase domain possesses a conserved active site but distinct surface properties. Binding to Rac1 induces a dramatic stabilization in SptP of a four-helix bundle that makes extensive contacts with the Switch I and Switch II regions of the GTPase.
Stebbins
C E
CE
Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of Medicine, New Haven, CT 06536, USA.
Galán
J E
JE
D017607:Aluminum Compounds / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D019143:Evolution, Molecular; D005459:Fluorides / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000737:chemistry* / Q000472:pathogenicity; D016415:Sequence Alignment; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
D017607:Aluminum Compounds; D001426:Bacterial Proteins; D020690:GTPase-Activating Proteins; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; D006153:Guanosine Diphosphate; D017027:Protein Tyrosine Phosphatases; C439890:sptP protein, Salmonella typhimurium; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D005459:Fluorides; C032311:aluminum fluoride