Solution Structure of NOD1 CARD and Mutational Analysis of its Interaction with the CARD of Downstream Kinase RICK

Manon, Florence; Favier, Adrien; Núñez, Gabriel; Simorre, Jean-Pierre; Cusack, Stephen

doi:10.1016/j.jmb.2006.09.067

Cited by 71 publications

(142 citation statements)

References 61 publications

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“…The overall structure of the Nod1 CARD was expected to be similar to the other CARD structures, as well as to the recently published NMR structure of the Nod1 CARD [13].…”

Section: Resultssupporting

confidence: 73%

“…Leucine 29 and 30 are involved in hydrophobic interactions with L100 and W103 of the other molecule. Interestingly, interactions found in the monomeric NMR structure of Nod1 CARD, between W103, F109, and residues around L22 in helix one [13], are preserved in the dimeric structure that we report here. The total buried surface area, calculated using surfvol [24], is about 3000 Å 2 for the dimer, with approximately 1500 Å 2 of each monomer being buried.…”

Section: Resultssupporting

confidence: 59%

“…A comparison of this structure with the structures of other known CARDs and with the NMR structure of Nod1 CARD [13] reveals differences that are possibly important for its function.…”

Section: Introductionmentioning

confidence: 88%

“…The domains are all characterized by a Greek key motif of six alpha helicies. Several structures have been determined for isolated CARDs: RAIDD [11], ICEBERG [12], and Nod1 [13] by NMR and APAF-1 by X-ray crystallography [14,15] and NMR [16,17]. A crystal structure was also determined for the heterodimeric complex of APAF-1 and procaspase-9 CARDs [15].…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of the Nod1 caspase activation and recruitment domain

Coussens

Mowers

McDonald

et al. 2007

Biochemical and Biophysical Research Communications

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Nod-like receptors (NLRs), Nod1 and Nod2 are cytosolic detectors of pathogen associated molecular patterns (PAMPs). Nod1 is a three-domain protein, consisting of a caspase activation and recruitment domain (CARD), a nucleotide-binding oligomerization domain (NOD), and a leucine-rich repeat domain (LRR). The binding of PAMPs to the LRR results in the activation of signaling through homophilic CARD-CARD interactions. Several CARD structures have been determined, including a recent NMR structure of Nod1 CARD. In contrast to the reported NMR structure, the crystal structure reported here is a dimer, where the sixth helix is swapped between two monomers. While the overall structure is very similar to the known CARD structures, this is the first report of a homodimeric CARD structure. The ability of the CARD to exist in monomeric and dimeric forms suggests another level of regulation in the activation of NLR proteins.

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“…The overall structure of the Nod1 CARD was expected to be similar to the other CARD structures, as well as to the recently published NMR structure of the Nod1 CARD [13].…”

Section: Resultssupporting

confidence: 73%

Section: Resultssupporting

confidence: 59%

“…A comparison of this structure with the structures of other known CARDs and with the NMR structure of Nod1 CARD [13] reveals differences that are possibly important for its function.…”

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Crystal structure of the Nod1 caspase activation and recruitment domain

Coussens

Mowers

McDonald

et al. 2007

Biochemical and Biophysical Research Communications

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“…To determine whether mutations in specific regions of NOD1 affect HCMV replication, we generated stable cell lines overexpressing wild-type (WT) NOD1 and two NOD1 mutants, E56K (in the CARD) and E266K (in the NBD), using a doxycycline-inducible lentivirus system. The E56K mutation was reported to abrogate NOD1 signaling by abolishing its interaction with RIPK2 (23,24), indicating a role for NOD1-RIPK2 interaction in executing downstream signaling. The E266K mutation in NOD1 has been suggested to increase the pathogenesis of Helicobacter pylori infection (25); however, its effect on NOD1 function remains undetermined.…”

Section: Nod1 Kd or Inhibition Of Its Activity Results In Enhanced Hcmvmentioning

confidence: 99%

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Fan

Roy

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotidebinding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-β expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2-IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.H uman cytomegalovirus (HCMV), a member of the herpesvirus family, induces complex innate immune responses (1, 2). Despite this effective and multifaceted induction, HCMV has developed strategies to counteract its recognition (3), allowing for its productive replication and the establishment of latency. Identification and characterization of HCMV-induced innate immune responses and resulting signaling pathways may provide novel strategies for its control.Mounting evidence indicates that HCMV sensing is an intricate process involving activities of membrane, cytoplasmic, and nuclear receptors. Several HCMV-encoded proteins directly activate innate immune response molecules; the glycoprotein B (gB) binds to and activates TLR2 (4), and pp65 interacts with IFI16 (5). Other viral proteins, dsDNA, or dsRNA are likely to activate or inhibit host innate response molecules. Several previous reports have highlighted a complex role of the IFN pathway in response to HCMV. The activity of the promyeolcytic leukemia protein, a regulator of type I IFN response, is counteracted by HCMV-encoded immediate early 1 protein (IE1) (6). A cytoplasmic dsDNA sensor, ZBP1, activates IRF3 on infection, and its overexpression inhibits HCMV replication (7). IFN-inducible protein IFI16 modestly in...

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Structural insights into the MDP binding and CARD-CARD interaction in zebrafish (Danio rerio) NOD2: a molecular dynamics approach

Maharana

Patra

et al. 2014

J. Mol. Recognit.

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Nucleotide binding and oligomerization domain (NOD2) is a key component of innate immunity that is highly specific for muramyl dipeptide (MDP)-a peptidoglycan component of bacterial cell wall. MDP recognition by NOD2-leucine rich repeat (LRR) domain activates NF-κB signaling through a protein-protein interaction between caspase activating and recruitment domains (CARDs) of NOD2 and downstream receptor interacting and activating protein kinase 2 (RIP2). Due to the lack of crystal/NMR structures, MDP recognition and CARD-CARD interaction are poorly understood. Herein, we have predicted the probable MDP and CARD-CARD binding surfaces in zebrafish NOD2 (zNOD2) using various in silico methodologies. The results show that the conserved residues Phe819, Phe871, Trp875, Trp929, Trp899, and Arg845 located at the concave face of zNOD2-LRR confer MDP recognition by hydrophobic and hydrogen bond (H-bond) interactions. Molecular dynamics simulations reveal a stable association between the electropositive surface on zNOD2-CARDa and the electronegative surface on zRIP2-CARD reinforced mostly by H-bonds and electrostatic interactions. Importantly, a 3.5 Å salt bridge is observed between Arg60 of zNOD2-CARDa and Asp494 of zRIP2-CARD. Arg11 and Lys53 of zNOD2-CARDa and Ser498 and Glu508 of zRIP2-CARD are critical residues for CARD-CARD interaction and NOD2 signaling. The 2.7 Å H-bond between Lys104 of the linker and Glu508 of zRIP2-CARD suggests a possible role of the linker for shaping CARD-CARD interaction. These findings are consistent with existing mutagenesis data. We provide first insight into MDP recognition and CARD-CARD interaction in the zebrafish that will be useful to understand the molecular basis of NOD signaling in a broader perspective.

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Solution Structure of NOD1 CARD and Mutational Analysis of its Interaction with the CARD of Downstream Kinase RICK

Cited by 71 publications

References 61 publications

Crystal structure of the Nod1 caspase activation and recruitment domain

Crystal structure of the Nod1 caspase activation and recruitment domain

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Structural insights into the MDP binding and CARD-CARD interaction in zebrafish (Danio rerio) NOD2: a molecular dynamics approach

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