Characterization of a TIR-like protein from Paracoccus denitrificans

Low, Lieh Yoon; Mukasa, Takashi; Reed, John C.; Pascual, Jaime

doi:10.1016/j.bbrc.2007.03.003

Cited by 26 publications

(31 citation statements)

References 14 publications

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“…Previously, we have shown, using size-exclusion chromatography, that the full-length PdTLP exists as a dimer, whereas PdTIR domain by itself is a monomer (15). We have further verified these observations using analytical ultracentrifugation techniques, which showed that PdTLP and PdTIR behave as dimer and monomer, respectively (data not shown).…”

Section: Dimerization Interfaces Of Pdtir As Observed Using Hydrogen-supporting

confidence: 73%

“…15) with the TIR domains of human TLR1, TLR2, TLR10, and MyD88, the overall fold of PdTIR is highly similar to these human proteins. A search using the Dali server (29) has identified the TIR domains of TLR1 and TLR10 as the closest structures to PdTIR with Z-score values of 10.8 and 10.4 and r.m.s.d.…”

Section: Resultsmentioning

confidence: 86%

“…Protein Sample Preparation-PdTLP was expressed in E. coli and purified as a homogenous dimer as described previously (15). The TIR domain (PdTIR) was cut from the full-length protein by chymotrypsin digestion (Sigma-Aldrich) and further purified by chromatographic methods using a Sephacryl S200 gel filtration column (GE Healthcare), where it eluted at the volume expected for a monomer.…”

Section: Methodsmentioning

confidence: 99%

“…2) with the buried surface covering an area of 593 Å 2 of molecule B and 609 Å 2 of molecule D. Analysis of this interface using the PISA server (25) recorded a complexation significance score value of 1.0, implying that this surface plays an essential role in complex formation. Although PdTIR exists as a monomer in solution, it is likely that this surface participates in the homodimerization process that the full-length protein (PdTLP) experiences in solution (15). The interaction between these two molecules mainly involves the DD-and EE-loops of both chain B and chain D (Fig.…”

Section: Dimerization Interfaces Of Pdtir As Observed In the Crystal-mentioning

confidence: 99%

“…The bacterial TIR primary sequence conservation is high with more than 50% sequence identity among members of the family but less than 20% with their mammalian counterparts. Our previous studies with a member of this family, the TIR-like protein (PdTLP) from Paracoccus denitrificans, have shown that it behaves as a homodimer in the full-length context, whereas the isolated TIR domain (PdTIR) is monomeric (15). In this study, we report the crystal structure of the TIR domain of P. denitrificans (PdTIR) and compare it with known TIR domain structures from human TLRs and its main adaptor MyD88.…”

mentioning

confidence: 99%

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Molecular Mimicry in Innate Immunity

Chan

Low

Hsu

et al. 2009

Journal of Biological Chemistry

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Macrophages detect pathogen infection via the activation of their plasma membrane-bound Toll-like receptor proteins (TLRs). The heterotypic interaction between the Toll/interleukin-1 receptor (TIR) domains of TLRs and adaptor proteins, likeMyeloid differentiation primary response gene 88 (MyD88), is the first intracellular step in the signaling pathway of the mammalian innate immune response. The hetero-oligomerization of the TIRs of the receptor and adaptor brings about the activation of the transcription factor NF-B, which regulates the synthesis of pro-inflammatory cytokines. Here, we report the first crystal structure of a bacterial TIR domain solved at 2.5 Å resolution. The three-dimensional fold of Paracoccus denitrificans TIR is identical to that observed for the TIR of human TLRs and MyD88 proteins. The structure shows a unique dimerization interface involving the DD-loop and EE-loop residues, whereas leaving the BB-loop highly exposed. Peptide amide hydrogendeuterium exchange mass spectrometry also reveals that the same region is used for dimerization in solution and in the context of the full-length protein. These results, together with a functional interaction between P. denitrificans TIR and MyD88 visualized in a co-immunoprecipitation assay, further substantiate the model that bacterial TIR proteins adopt structural mimicry of the host active receptor TIR domains to interfere with the signaling of TLRs and their adaptors to decrease the inflammatory response. Toll/interleukin-1 receptor (TIR)2 domain is a key mediator in the Toll-like receptor (TLR) signaling. TLRs are involved in early detection of pathogen-associated molecular patterns to enable quick responses to infection by triggering innate immune reactions through activation of the gene program regulated by the transcription factor nuclear factor-B (NF-B) and the recruitment of macrophages to the infection sites (1). The signaling of TLRs requires the homo-or heterodimerization of their extracellular leucine-rich repeats region mediated by the microbial pathogen-associated molecular patterns, leading to the dimerization of the receptor cytoplasmic TIR domains (2). Only in this active conformation are the receptor TIR domains capable of a functionally productive interaction with TIR domains of adaptor molecules, such as Myeloid differentiation primary response gene 88 (MyD88), MyD88 adaptor-like (Mal, also known as Toll/IL-1 receptor domain-containing adaptor protein (TIRAP)), TIR domain-containing adapter-inducing interferon-␤ (TRIF), or TRIF-related adaptor molecule (TRAM), to initiate the signaling cascade (3).Structures of TIR domains from human TLR1(4), TLR2(5), TLR10(6), IL-1RAPL(7), and MyD88 (Protein Data Bank (PDB) IDs: 2JS7; 2Z5V) have been determined, and they all showed a flavodoxin-like fold consisting of three layers ␣/␤/␣ with fivestranded parallel ␤-sheet ordered 2,1,3,4,5 surrounded by ␣-helices on each side. However, neither the homotypic interactions of TIR domains nor the heterotypic ones between the TIRs of receptors and a...

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Section: Dimerization Interfaces Of Pdtir As Observed Using Hydrogen-supporting

confidence: 73%

Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Dimerization Interfaces Of Pdtir As Observed In the Crystal-mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Mimicry in Innate Immunity

Chan

Low

Hsu

et al. 2009

Journal of Biological Chemistry

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Regulation of Immunity and Disease by the IL-1 Receptor Family Members IL-1R2 and IL-1R8

Molgora

Supino

Garlanda

2018

Immunopharmacology and Inflammation

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Bacterial TIR-containing proteins and host innate immune system evasion

Rana

Zhang

Spear

et al. 2012

Med Microbiol Immunol

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The innate immune system provides the first line of host defence against invading pathogens. Key to upregulation of the innate immune response are Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and trigger a signaling pathway culminating in the production of inflammatory mediators. Central to this TLR signaling pathway are heterotypic protein-protein interactions mediated through Toll/interleukin-1 receptor (TIR) domains found in both the cytoplasmic regions of TLRs and adaptor proteins. Pathogenic bacteria have developed a range of ingenuous strategies to evade the host immune mechanisms. Recent work has identified a potentially novel evasion mechanism involving bacterial TIR domain proteins. Such domains have been identified in a wide range of pathogenic bacteria, and there is evidence to suggest that they interfere directly with the TLR signaling pathway and thus inhibit the activation of NF-κB. The individual TIR domains from the pathogenic bacteria Salmonella enterica serovar Enteritidis, Brucella sp, uropathogenic E. coli and Yersinia pestis have been analyzed in detail. The individual bacterial TIR domains from these pathogenic bacteria seem to differ in their modes of action and their roles in virulence. Here, we review the current state of knowledge on the possible roles and mechanisms of action of the bacterial TIR domains.

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Characterization of a TIR-like protein from Paracoccus denitrificans

Cited by 26 publications

References 14 publications

Molecular Mimicry in Innate Immunity

Molecular Mimicry in Innate Immunity

Regulation of Immunity and Disease by the IL-1 Receptor Family Members IL-1R2 and IL-1R8

Bacterial TIR-containing proteins and host innate immune system evasion

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