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Lih Ling Lin - One of the best experts on this subject based on the ideXlab platform.
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Solution structure of the tumor necrosis factor receptor-1 Death Domain.
Journal of molecular biology, 2001Co-Authors: Steven F. Sukits, Lih Ling Lin, Sang Hsu, Karl Malakian, Robert PowersAbstract:Abstract Tumor necrosis factor receptor-1 Death Domain (TNFR-1 DD) is the intracellular functional Domain responsible for the receptor signaling activities. The solution structure of the R347K mutant of TNFR-1 DD was solved by NMR spectroscopy. A total of 20 structures were calculated by means of hybrid distance geometry-simulated annealing using a total of 1167 distance constraints and 117 torsion angle constraints. The atomic rms distribution about the mean coordinate positions for the 20 structures for residues composing the secondary structure region is 0.40 A for the backbone atoms and 1.09 A for all atoms. The structure consists of six antiparallel α-helices arranged in a similar fashion to the other members of the Death Domain superfamily. The secondary structure and three-dimensional structure of R347K TNFR1-DD are very similar to the secondary structure and deduced topology of the R347A TNFR1-DD mutant. Mutagenesis studies identified critical residues located in α2 and part of α3 and α4 that are crucial for self-interaction and interaction with TRADD. Structural superposition with previously solved proteins in the Death Domain superfamily reveals that the major differences between the structures reside in α2, α3, and α4. Interestingly, these regions correspond to the binding sites of TNFR1-DD, providing a structural basis for the specificity of Death Domain interactions and its subsequent signaling event.
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Mutational analysis and NMR studies of the Death Domain of the tumor necrosis factor receptor-1.
Journal of molecular biology, 2000Co-Authors: Jean-baptiste Telliez, Steven F. Sukits, Sang Hsu, Robert Powers, John D. Woronicz, Laura Lin, Lih Ling LinAbstract:Abstract Tumor necrosis factor receptor-1 (TNFR-1) Death Domain (DD) is the intracellular functional Domain responsible for the receptor signaling activities. To understand the transduction mechanism of TNFR-1 signaling we performed structural and functional analysis of the TNFR-DD. The secondary structure of the TNFR-DD shows that it consists of six anti-parallel α-helices. The determination of the topological fold and an extensive mutagenesis analysis revealed that there are two opposite faces that are involved in self-association and interaction with the TRADD Death Domain. Interestingly, the same critical residues in TNFR-DD are involved in both interactions. There is a good correlation between the binding activities of the mutant proteins and their cytotoxic activities. These results provide important insight into the molecular interactions mediating TNFR-DD self-association and subsequent recruitment of TRADD in the signaling activity of TNFR-1.
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LRDD, a novel leucine rich repeat and Death Domain containing protein.
Biochimica et biophysica acta, 2000Co-Authors: Jean-baptiste Telliez, Kevin M. Bean, Lih Ling LinAbstract:Abstract Death Domains (DD) and leucine rich repeats (LRR) are two different types of protein interaction motifs. Death Domains are found predominantly in proteins involved in signaling and are involved in homo- and heteromultimerization. Leucine rich repeats are found in proteins with diverse cellular functions, like cell adhesion and cellular signaling, and mediate reversible protein–protein interactions. In this paper we report the cloning of a new human gene called LRDD (leucine repeat Death Domain containing protein). LRDD encodes a protein of 83 kDa with six LRRs at the N-terminus and a DD at the C-terminus. LRDD appears to be processed into two fragments of about 33 and 55 kDa, containing LRRs and DD respectively. Interestingly, LRDD is shown to interact with two other Death Domain containing proteins, FADD and MADD, presumably through Death Domain interactions. LRDD may represent a new type of adapter protein that could be involved in signaling or other cellular functions.
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MADD, A NOVEL Death Domain PROTEIN THAT INTERACTS WITH THE TYPE 1 TUMOR NECROSIS FACTOR RECEPTOR AND ACTIVATES MITOGEN-ACTIVATED PROTEIN KINASE
The Journal of biological chemistry, 1997Co-Authors: Andrea R. Schievella, Jennifer Chen, James Graham, Lih Ling LinAbstract:The Death Domain of the type 1 tumor necrosis factor receptor (TNFR1) mediates interactions with several proteins involved in signaling the downstream effects of TNF. We have used the yeast interaction trap to isolate a protein, MADD, that associates with the Death Domain of TNFR1 through its own C-terminal Death Domain. MADD interacts with TNFR1 residues that are critical for signal generation and coimmunoprecipitates with TNFR1, implicating MADD as a component of the TNFR1 signaling complex. Importantly, we have found that overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK), and expression of the MADD Death Domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2. These data indicate that MADD links TNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects.
Vishva M. Dixit - One of the best experts on this subject based on the ideXlab platform.
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Identification of a novel Death Domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice.
Current biology : CB, 2002Co-Authors: Minhong Yan, Wayne J. Fairbrother, Zemin Zhang, John Ridgway Brady, Sarah Schilbach, Vishva M. DixitAbstract:Hypohydrotic Ectodermal Dysplasia (HED) is a genetic disease seen in humans and mice. It is characterized by loss of hair, sweat glands, and teeth. The predominant X-linked form results from mutations in ectodysplasin-A (EDA), a TNF-like ligand. A phenotypically indistinguishable autosomal form of the disease results from mutations in the receptor for EDA (EDAR). EDAR is a NF-kappaB-activating, Death Domain-containing member of the TNF receptor family. crinkled, a distinct autosomal form of HED, was discovered in a mouse strain in which both the ligand (EDA) and receptor (EDAR) were wild-type, suggestive of a disruption further downstream in the signaling pathway. Employing a forward genetic approach, we have cloned crinkled (CR) and find it to encode a novel Death Domain-containing adaptor. crinkled binds EDAR through a homotypic Death Domain interaction and mediates engagement of the NF-kappaB pathway, possibly by recruiting TRAF2 to the receptor-signaling complex. This is an unprecedented example of naturally occurring mutations in ligand, receptor, or adaptor giving rise to the same phenotypic disease characterized by a defect in the proper development of epidermal appendages.
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The PYRIN Domain: a member of the Death Domain-fold superfamily.
Protein science : a publication of the Protein Society, 2001Co-Authors: Wayne J. Fairbrother, Karen O'rourke, Nathaniel C. Gordon, Eric W. Humke, Melissa A. Starovasnik, Jianping Yin, Vishva M. DixitAbstract:PYRIN Domains were identified recently as putative protein–protein interaction Domains at the N-termini of several proteins thought to function in apoptotic and inflammatory signaling pathways. The ∼95 residue PYRIN Domains have no statistically significant sequence homology to proteins with known three-dimensional structure. Using secondary structure prediction and potential-based fold recognition methods, however, the PYRIN Domain is predicted to be a member of the six-helix bundle Death Domain-fold superfamily that includes Death Domains (DDs), Death effector Domains (DEDs), and caspase recruitment Domains (CARDs). Members of the Death Domain-fold superfamily are well established mediators of protein–protein interactions found in many proteins involved in apoptosis and inflammation, indicating further that the PYRIN Domains serve a similar function. An homology model of the PYRIN Domain of CARD7/DEFCAP/NAC/NALP1, a member of the Apaf-1/Ced-4 family of proteins, was constructed using the three-dimensional structures of the FADD and p75 neurotrophin receptor DDs, and of the Apaf-1 and caspase-9 CARDs, as templates. Validation of the model using a variety of computational techniques indicates that the fold prediction is consistent with the sequence. Comparison of a circular dichroism spectrum of the PYRIN Domain of CARD7/DEFCAP/NAC/NALP1 with spectra of several proteins known to adopt the Death Domain-fold provides experimental support for the structure prediction.
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identification and functional characterization of dr6 a novel Death Domain containing tnf receptor
FEBS Letters, 1998Co-Authors: Guohua Pan, Claudius Vincenz, Bharat B. Aggarwal, Johannes H Bauer, Valsala Haridas, Shuxia Wang, Ding Liu, Vishva M. DixitAbstract:Tumor nectosis factor (TNF) receptors are key players in inflammation and immune regulation. A new member of this family, termed Death receptor-6 (DR6), has been identified. Like other Death receptors, DR6 is a type I transmembrane receptor, possesses four extracellular cysteine-rich motifs and a cytoplasmic Death Domain. DR6 is expressed in most human tissues and abundant transcript was detected in heart, brain, placenta, pancreas, thymus, lymph node and several non-lymphoid cancer cell lines. DR6 interacts with TRADD, which has previously been shown to associate with TNFR1. Furthermore, ectopic expression of DR6 in mammalian cells induces apoptosis and activation of both NF-κB and JNK.
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An antagonist decoy receptor and a Death Domain-containing receptor for TRAIL
Science (New York N.Y.), 1997Co-Authors: Guohua Pan, Ying Fei Wei, Reiner L. Gentz, Vishva M. DixitAbstract:TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its Death Domain-containing receptor, DR4, is expressed on both cell types. An antagonist decoy receptor (designated as TRID for TRAIL receptor without an intracellular Domain) that may explain the resistant phenotype of normal tissues was identified. TRID is a distinct gene product with an extracellular TRAIL-binding Domain and a transmembrane Domain but no intracellular signaling Domain. TRID transcripts were detected in many normal human tissues but not in most cancer cell lines examined. Ectopic expression of TRID protected mammalian cells from TRAIL-induced apoptosis, which is consistent with a protective role. Another Death Domain-containing receptor for TRAIL (designated as Death receptor-5), which preferentially engaged a FLICE (caspase-8)-related Death protease, was also identified.
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Signal Transduction by DR3, a Death Domain-Containing Receptor Related to TNFR-1 and CD95
Science (New York N.Y.), 1996Co-Authors: Arul M. Chinnaiyan, Karen O'rourke, Reiner L. Gentz, Robert H. Lyons, Manish Garg, D. Roxanne Duan, Lily Xing, Vishva M. DixitAbstract:Tumor necrosis factor receptor-1 (TNFR-1) and CD95 (also called Fas or APO-1) are cytokine receptors that engage the apoptosis pathway through a region of intracellular homology, designated the “Death Domain.” Another Death Domain-containing member of the TNFR family, Death receptor 3 (DR3), was identified and was shown to induce both apoptosis and activation of nuclear factor κB. Expression of DR3 appears to be restricted to tissues enriched in lymphocytes. DR3 signal transduction is mediated by a complex of intracellular signaling molecules including TRADD, TRAF2, FADD, and FLICE. Thus, DR3 likely plays a role in regulating lymphocyte homeostasis.
Robert Powers - One of the best experts on this subject based on the ideXlab platform.
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Solution structure of the tumor necrosis factor receptor-1 Death Domain.
Journal of molecular biology, 2001Co-Authors: Steven F. Sukits, Lih Ling Lin, Sang Hsu, Karl Malakian, Robert PowersAbstract:Abstract Tumor necrosis factor receptor-1 Death Domain (TNFR-1 DD) is the intracellular functional Domain responsible for the receptor signaling activities. The solution structure of the R347K mutant of TNFR-1 DD was solved by NMR spectroscopy. A total of 20 structures were calculated by means of hybrid distance geometry-simulated annealing using a total of 1167 distance constraints and 117 torsion angle constraints. The atomic rms distribution about the mean coordinate positions for the 20 structures for residues composing the secondary structure region is 0.40 A for the backbone atoms and 1.09 A for all atoms. The structure consists of six antiparallel α-helices arranged in a similar fashion to the other members of the Death Domain superfamily. The secondary structure and three-dimensional structure of R347K TNFR1-DD are very similar to the secondary structure and deduced topology of the R347A TNFR1-DD mutant. Mutagenesis studies identified critical residues located in α2 and part of α3 and α4 that are crucial for self-interaction and interaction with TRADD. Structural superposition with previously solved proteins in the Death Domain superfamily reveals that the major differences between the structures reside in α2, α3, and α4. Interestingly, these regions correspond to the binding sites of TNFR1-DD, providing a structural basis for the specificity of Death Domain interactions and its subsequent signaling event.
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Mutational analysis and NMR studies of the Death Domain of the tumor necrosis factor receptor-1.
Journal of molecular biology, 2000Co-Authors: Jean-baptiste Telliez, Steven F. Sukits, Sang Hsu, Robert Powers, John D. Woronicz, Laura Lin, Lih Ling LinAbstract:Abstract Tumor necrosis factor receptor-1 (TNFR-1) Death Domain (DD) is the intracellular functional Domain responsible for the receptor signaling activities. To understand the transduction mechanism of TNFR-1 signaling we performed structural and functional analysis of the TNFR-DD. The secondary structure of the TNFR-DD shows that it consists of six anti-parallel α-helices. The determination of the topological fold and an extensive mutagenesis analysis revealed that there are two opposite faces that are involved in self-association and interaction with the TRADD Death Domain. Interestingly, the same critical residues in TNFR-DD are involved in both interactions. There is a good correlation between the binding activities of the mutant proteins and their cytotoxic activities. These results provide important insight into the molecular interactions mediating TNFR-DD self-association and subsequent recruitment of TRADD in the signaling activity of TNFR-1.
Bok Jang - One of the best experts on this subject based on the ideXlab platform.
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Death Domain complex of the TNFR-1, TRADD, and RIP1 proteins for Death-inducing signaling
Biochemical and biophysical research communications, 2013Co-Authors: Young-hoon Park, Mi Suk Jeong, Bok JangAbstract:Apoptosis can be induced by an extrinsic pathway involving the ligand-mediated activation of Death receptors such as tumor necrosis factor receptor-1 (TNFR-1). TNFR-1-associated Death Domain (TRADD) protein is an adapter molecule that bridges the interaction between TNFR-1 and receptor-interacting serine/threonine-protein kinase 1 (RIP1). However, the molecular mechanism of the complex formation of these proteins has not yet been identified. Here, the binding among TNFR-1, TRADD, and RIP1 was identified using a GST pull-down assay and Biacore biosensor experiment. This study showed that structural characterization and formation of the Death-signaling complex could be predicted using TNFR-1, TRADD, and RIP1. In addition, we found that the structure-based mutations of TNFR-1 (P367A and P368A), TRADD (F266A), and RIP1 (M637A and R638A) disrupted formation of the Death Domain (DD) complex and prevented stable interactions among those DDs.
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Overexpression and Biological Characterization of the Death Domain Complex between TRADD and FADD
Bulletin of the Korean Chemical Society, 2013Co-Authors: Eun Young Hwang, Mi Suk Jeong, Min Kyung Sung, Bok JangAbstract:The tumor necrosis factor-receptor 1 (TNFR1)-associated Death Domain protein (TRADD) contains an N-terminal TRAF binding Domain and a C-terminal Death Domain. TRADD is known to interact directly with TNF receptor 2 (TNFR2) and the Fas-associated Death Domain protein (FADD), which are signal transducers that activate NF- and induce apoptosis, respectively. To date, there has been no structural information on the TRADD and FADD Death Domain (DDs) complex. In this study, the Death Domains of TRADD and FADD were co-expressed and purified from Escherichia coli for structural characterization. We found that human TRADD (hTRADD) interacted strongly with mouse FADD (mFADD) via their DDs and interacted weakly with human FADD (hFADD)-DD. Moreover, the structures of the TRADD-DD:FADD-DD complexes were separately modeled from predicted structures in the protein data bank (PDB). The results of this study will have important applications in human diseases such as cancer, AIDS, degenerative and autoimmune diseases, and infectious diseases.
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Formation of the Death Domain complex between FADD and RIP1 proteins in vitro.
Biochimica et biophysica acta, 2012Co-Authors: Young-hoon Park, Hyun Ho Park, Mi Suk Jeong, Bok JangAbstract:Fas-associated Death Domain (FADD) protein is an adapter molecule that bridges the interactions between membrane Death receptors and initiator caspases. The Death receptors contain an intracellular Death Domain (DD) which is essential to the transduction of the apoptotic signal. The kinase receptor-interacting protein 1 (RIP1) is crucial to programmed necrosis. The cell type interplay between FADD and RIP1, which mediates both necrosis and NF-κB activation, has been evaluated in other studies, but the mechanism of the interaction of the FADD and RIP1 proteins remain poorly understood. Here, we provided evidence indicating that the DD of human FADD binds to the DD of RIP1 in vitro. We developed a molecular docking model using homology modeling based on the structures of FADD and RIP1. In addition, we found that two structure-based mutants (G109A and R114A) of the FADD DD were able to bind to the RIP1 DD, and two mutations (Q169A and N171A) of FADD DD and four mutations (G595, K596, E620, and D622) of RIP1 DD disrupted the FADD-RIP1 interaction. Six mutations (Q169A, N171A, G595, K596, E620, and D622) lowered the stability of the FADD-RIP1 complex and induced aggregation that structurally destabilized the complex, thus disrupting the interaction.
Miroslaw Cygler - One of the best experts on this subject based on the ideXlab platform.
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Salmonella Effectors SseK1 and SseK3 Target Death Domain Proteins in the TNF and TRAIL Signaling Pathways.
Molecular & cellular proteomics : MCP, 2019Co-Authors: Joshua P. M. Newson, Nichollas E Scott, Cristina Giogha, Ivy Yeuk Wah Chung, Tania Wong Fok Lung, Jiyao Gan, Nancy Wang, Richard A. Strugnell, Nathaniel Francis Brown, Miroslaw CyglerAbstract:Strains of Salmonella utilize two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian Death Domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc glycopeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, whereas ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the Death Domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the Death Domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggest that salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of Death receptor signaling.
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Salmonella effectors SseK1 and SseK3 target Death Domain proteins in the TNF and TRAIL signaling pathways
2018Co-Authors: Joshua P. M. Newson, Nichollas E Scott, Cristina Giogha, Ivy Yeuk Wah Chung, Tania Wong Fok Lung, Nancy Wang, Richard A. Strugnell, Nathaniel Francis Brown, Miroslaw Cygler, Jaclyn S PearsonAbstract:Strains of Salmonella utilise two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian Death Domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc glycopeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, while ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the Death Domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the Death Domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggests that Salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of Death receptor signaling.
