Title |
Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli
|
---|---|
Published in |
Proceedings of the National Academy of Sciences of the United States of America, April 2013
|
DOI | 10.1073/pnas.1215770110 |
Pubmed ID | |
Authors |
Greg A. Snyder, Christine Cirl, Jiansheng Jiang, Kang Chen, Anna Waldhuber, Patrick Smith, Franziska Römmler, Nathaniel Snyder, Theresa Fresquez, Susanne Dürr, Nico Tjandra, Thomas Miethke, Tsan Sam Xiao |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 1% |
Turkey | 1 | 1% |
Poland | 1 | 1% |
Unknown | 87 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 20 | 22% |
Researcher | 14 | 16% |
Professor > Associate Professor | 8 | 9% |
Professor | 6 | 7% |
Student > Master | 6 | 7% |
Other | 18 | 20% |
Unknown | 18 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 28 | 31% |
Biochemistry, Genetics and Molecular Biology | 21 | 23% |
Immunology and Microbiology | 6 | 7% |
Chemistry | 4 | 4% |
Medicine and Dentistry | 2 | 2% |
Other | 8 | 9% |
Unknown | 21 | 23% |