title: Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli.
abstract: The Toll/IL-1 receptor (TIR) domains are crucial signaling modules during innate immune responses involving the Toll-like receptors (TLRs) and IL-1 receptor (IL-1R). Myeloid differential factor 88 (MyD88) is a central TIR domain-containing adapter molecule responsible for nearly all TLR-mediated signaling and is targeted by a TIR domain-containing protein C (TcpC) from virulent uropathogenic Escherichia coli, a common human pathogen. The mechanism of such molecular antagonism has remained elusive. We present the crystal structure of the MyD88 TIR domain with distinct loop conformations that underscore the functional specialization of the adapter, receptor, and microbial TIR domains. Our structural analyses shed light on the genetic mutations at these loops as well as the Poc site. We demonstrate that TcpC directly associates with MyD88 and TLR4 through its predicted DD and BB loops to impair the TLR-induced cytokine induction. Furthermore, NMR titration experiments identify the unique CD, DE, and EE loops from MyD88 at the TcpC-interacting surface, suggesting that TcpC specifically engages these MyD88 structural elements for immune suppression. These findings thus provide a molecular basis for the subversion of TLR signaling by the uropathogenic E. coli virulence factor TcpC and furnish a framework for the design of novel therapeutic agents that modulate immune activation.
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Snyder
authors.forename: Christine
authors.initials: C
authors.lastname: Cirl
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Jiang
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Waldhuber
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Franziska
authors.initials: F
authors.lastname: Römmler
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Snyder
authors.forename: Theresa
authors.initials: T
authors.lastname: Fresquez
authors.forename: Susanne
authors.initials: S
authors.lastname: Dürr
authors.forename: Nico
authors.initials: N
authors.lastname: Tjandra
authors.forename: Thomas
authors.initials: T
authors.lastname: Miethke
authors.forename: Tsan Sam
authors.initials: TS
authors.lastname: Xiao
mesh_terms: D003461:Crystallography; D004926:Escherichia coli / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008156:Luciferases; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D017472:Receptors, Interleukin-1 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D029968:Escherichia coli Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C549538:TcpC protein, E coli; D051193:Toll-Like Receptors; D037521:Virulence Factors; D008156:Luciferases