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Konstantin S. Mineev - One of the best experts on this subject based on the ideXlab platform.
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CARD Domain of rat RIP2 kinase: Refolding, solution structure, pH-dependent behavior and protein-protein interactions
PloS one, 2018Co-Authors: Sergey A. Goncharuk, Lilya E. Artemieva, Valentin M. Tabakmakher, Alexander S. Arseniev, Konstantin S. MineevAbstract:RIP2, one of the RIP kinases, interacts with p75 neurotrophin receptor, regulating the neuron survival, and with NOD1 and NOD2 proteins, causing the innate immune response against gram-negative and gram-positive bacteria via its caspase recruitment Domain (CARD). This makes RIP2 a prospective target for novel therapies, aimed to modulate the inflammatory diseases and neurogenesis/neurodegeneration. Several studies report the problems with the stability of human RIP2 CARD and its production in bacterial hosts, which is a prerequisite for the structural investigation with solution NMR spectroscopy. In the present work, we report the high yield production and refolding protocols and resolve the structure of rat RIP2 CARD. The structure reveals the important differences to the previously published conformation of the homologous human protein. Using solution NMR, we characterized the intramolecular mobility and pH-dependent behavior of RIP2 CARD, and found the propensity of the protein to form high-order oligomers at physiological pH while being monomeric under acidic conditions. The oligomerization of protein may be explained, based on the electrostatic properties of its surface. Analysis of the structure and sequences of homologous proteins reveals the residues which are significant for the unusual fold of RIP2 CARD Domains from different species. The high-throughput protein production/refolding protocols and proposed explanation for the protein oligomerization, provide an opportunity to design the stabilized variants of RIP2 CARD, which could be used to study the structural details of RIP2/NOD1/NOD2 interaction and perform the rational drug design.
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CARD Domain of rat RIP2 kinase: Refolding, solution structure, pH-dependent behavior and protein-protein interactions - Fig 1
2018Co-Authors: Sergey A. Goncharuk, Lilya E. Artemieva, Valentin M. Tabakmakher, Alexander S. Arseniev, Konstantin S. MineevAbstract:A - 1H,15N-HSQC spectrum of 300 μM RIP2CARD acquired at pH 4.5, 30°C. Sidechain NH2 groups of Asn and Gln are indicated by thick red lines and folded peaks from the Hε/Nε groups of Arg are marked by asterisks. The assignment is shown on the spectrum, peaks from the polyhistidine tag (MHHHHHHGSGSGLVPRGS) have numbers 1–18. B—The effective rotational correlation times of RIP2CARD N-H vectors, measured based on the cross-correlated relaxation rates.
Emad S Alnemri - One of the best experts on this subject based on the ideXlab platform.
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the pyrin CARD protein asc is an activating adaptor for caspase 1
Journal of Biological Chemistry, 2002Co-Authors: Srinivasa M Srinivasula, Jean-luc Poyet, Marjaneh Razmara, Pinaki Datta, Zhijia Zhang, Emad S AlnemriAbstract:The PYRIN and CARD Domains are members of the six-helix bundle death Domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN Domain, with procaspase-1 induced activation of procaspase-1 and processing of pro-interleukin-1beta in transfected cells. Substitution of the PYRIN Domain of ASC with an inducible FKBP12 oligomerization Domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN Domain functions as an oligomerization Domain, whereas the CARD Domain functions as the effector Domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1beta generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.
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CARD 8 protein a new CARD family member that regulates caspase 1 activation and apoptosis
Journal of Biological Chemistry, 2002Co-Authors: Marjaneh Razmara, Jean-luc Poyet, John Bertin, Peter S Distefano, Lin Wang, Srinivasa M Srinivasula, Brad J Geddes, Emad S AlnemriAbstract:Caspase-associated recruitment Domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFκB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD Domain with high similarity to the CARD Domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1β generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD Domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-κB activation by TNF-α stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-κB activation.
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CARD10 is a novel caspase recruitment Domain membrane associated guanylate kinase family member that interacts with bcl10 and activates nf κb
Journal of Biological Chemistry, 2001Co-Authors: Lin Wang, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Emad S Alnemri, Yin Guo, Waanjeng Huang, Gulam A Manji, Alexandra M Glucksmann, John BertinAbstract:Abstract BCL10 belongs to the caspase recruitment Domain (CARD) family of proteins that regulate apoptosis and NF-κB signaling pathways. Analysis of BCL10-deficient mice has revealed that BCL10 mediates NF-κB activation by antigen receptors in B and T cells. We recently identified a subclass of CARD proteins (CARD9, CARD11, and CARD14) that may function to connect BCL10 to multiple upstream signaling pathways. We report here that CARD10 is a novel BCL10 interactor that belongs to the membrane-associated guanylate kinase family, a class of proteins that function to organize signaling complexes at plasma membranes. When expressed in cells, CARD10 binds to BCL10 and signals the activation of NF-κB through its N-terminal effector CARD Domain. We propose that CARD10 functions as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-κB.
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CARD11 and CARD14 Are Novel Caspase Recruitment Domain (CARD)/Membrane-associated Guanylate Kinase (MAGUK) Family Members that Interact with BCL10 and Activate NF-κB
Journal of Biological Chemistry, 2001Co-Authors: John Bertin, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Michael D. Jacobson, Lin Wang, Emad S AlnemriAbstract:Abstract The caspase recruitment Domain (CARD) is a protein-binding module that mediates the assembly of CARD-containing proteins into apoptosis and NF-κB signaling complexes. We report here that CARD protein 11 (CARD11) and CARD protein 14 (CARD14) are novel CARD-containing proteins that belong to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. CARD11 and CARD14 have homologous structures consisting of an N-terminal CARD Domain, a central coiled-coil Domain, and a C-terminal tripartite Domain comprised of a PDZ Domain, an Src homology 3 Domain, and a GUK Domain with homology to guanylate kinase. The CARD Domains of both CARD11 and CARD14 associate specifically with the CARD Domain of BCL10, a signaling protein that activates NF-κB through the IκB kinase complex in response to upstream stimuli. When expressed in cells, CARD11 and CARD14 activate NF-κB and induce the phosphorylation of BCL10. These findings suggest that CARD11 and CARD14 are novel MAGUK family members that function as upstream activators of BCL10 and NF-κB signaling.
John Bertin - One of the best experts on this subject based on the ideXlab platform.
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autolytic proteolysis within the function to find Domain fiind is required for nlrp1 inflammasome activity
Journal of Biological Chemistry, 2012Co-Authors: Joshua N Finger, John Bertin, John D Lich, Lauren Dare, Michael N Cook, Kristin K Brown, Chaya Duraiswami, Peter J GoughAbstract:Nucleotide-binding Domain leucine-rich repeat proteins (NLRs) play a key role in immunity and disease through their ability to modulate inflammation in response to pathogen-derived and endogenous danger signals. Here, we identify the requirements for activation of NLRP1, an NLR protein associated with a number of human pathologies, including vitiligo, rheumatoid arthritis, and Crohn disease. We demonstrate that NLRP1 activity is dependent upon ASC, which associates with the C-terminal CARD Domain of NLRP1. In addition, we show that NLRP1 activity is dependent upon autolytic cleavage at Ser1213 within the FIIND. Importantly, this post translational event is dependent upon the highly conserved distal residue His1186. A disease-associated single nucleotide polymorphism near His1186 and a naturally occurring mRNA splice variant lacking exon 14 differentially affect this autolytic processing and subsequent NLRP1 activity. These results describe key molecular pathways that regulate NLRP1 activity and offer insight on how small sequence variations in NLR genes may influence human disease pathogenesis.
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CARD 8 protein a new CARD family member that regulates caspase 1 activation and apoptosis
Journal of Biological Chemistry, 2002Co-Authors: Marjaneh Razmara, Jean-luc Poyet, John Bertin, Peter S Distefano, Lin Wang, Srinivasa M Srinivasula, Brad J Geddes, Emad S AlnemriAbstract:Caspase-associated recruitment Domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFκB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD Domain with high similarity to the CARD Domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1β generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD Domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-κB activation by TNF-α stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-κB activation.
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CARD10 is a novel caspase recruitment Domain membrane associated guanylate kinase family member that interacts with bcl10 and activates nf κb
Journal of Biological Chemistry, 2001Co-Authors: Lin Wang, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Emad S Alnemri, Yin Guo, Waanjeng Huang, Gulam A Manji, Alexandra M Glucksmann, John BertinAbstract:Abstract BCL10 belongs to the caspase recruitment Domain (CARD) family of proteins that regulate apoptosis and NF-κB signaling pathways. Analysis of BCL10-deficient mice has revealed that BCL10 mediates NF-κB activation by antigen receptors in B and T cells. We recently identified a subclass of CARD proteins (CARD9, CARD11, and CARD14) that may function to connect BCL10 to multiple upstream signaling pathways. We report here that CARD10 is a novel BCL10 interactor that belongs to the membrane-associated guanylate kinase family, a class of proteins that function to organize signaling complexes at plasma membranes. When expressed in cells, CARD10 binds to BCL10 and signals the activation of NF-κB through its N-terminal effector CARD Domain. We propose that CARD10 functions as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-κB.
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CARD11 and CARD14 Are Novel Caspase Recruitment Domain (CARD)/Membrane-associated Guanylate Kinase (MAGUK) Family Members that Interact with BCL10 and Activate NF-κB
Journal of Biological Chemistry, 2001Co-Authors: John Bertin, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Michael D. Jacobson, Lin Wang, Emad S AlnemriAbstract:Abstract The caspase recruitment Domain (CARD) is a protein-binding module that mediates the assembly of CARD-containing proteins into apoptosis and NF-κB signaling complexes. We report here that CARD protein 11 (CARD11) and CARD protein 14 (CARD14) are novel CARD-containing proteins that belong to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. CARD11 and CARD14 have homologous structures consisting of an N-terminal CARD Domain, a central coiled-coil Domain, and a C-terminal tripartite Domain comprised of a PDZ Domain, an Src homology 3 Domain, and a GUK Domain with homology to guanylate kinase. The CARD Domains of both CARD11 and CARD14 associate specifically with the CARD Domain of BCL10, a signaling protein that activates NF-κB through the IκB kinase complex in response to upstream stimuli. When expressed in cells, CARD11 and CARD14 activate NF-κB and induce the phosphorylation of BCL10. These findings suggest that CARD11 and CARD14 are novel MAGUK family members that function as upstream activators of BCL10 and NF-κB signaling.
Sergey A. Goncharuk - One of the best experts on this subject based on the ideXlab platform.
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CARD Domain of rat RIP2 kinase: Refolding, solution structure, pH-dependent behavior and protein-protein interactions
PloS one, 2018Co-Authors: Sergey A. Goncharuk, Lilya E. Artemieva, Valentin M. Tabakmakher, Alexander S. Arseniev, Konstantin S. MineevAbstract:RIP2, one of the RIP kinases, interacts with p75 neurotrophin receptor, regulating the neuron survival, and with NOD1 and NOD2 proteins, causing the innate immune response against gram-negative and gram-positive bacteria via its caspase recruitment Domain (CARD). This makes RIP2 a prospective target for novel therapies, aimed to modulate the inflammatory diseases and neurogenesis/neurodegeneration. Several studies report the problems with the stability of human RIP2 CARD and its production in bacterial hosts, which is a prerequisite for the structural investigation with solution NMR spectroscopy. In the present work, we report the high yield production and refolding protocols and resolve the structure of rat RIP2 CARD. The structure reveals the important differences to the previously published conformation of the homologous human protein. Using solution NMR, we characterized the intramolecular mobility and pH-dependent behavior of RIP2 CARD, and found the propensity of the protein to form high-order oligomers at physiological pH while being monomeric under acidic conditions. The oligomerization of protein may be explained, based on the electrostatic properties of its surface. Analysis of the structure and sequences of homologous proteins reveals the residues which are significant for the unusual fold of RIP2 CARD Domains from different species. The high-throughput protein production/refolding protocols and proposed explanation for the protein oligomerization, provide an opportunity to design the stabilized variants of RIP2 CARD, which could be used to study the structural details of RIP2/NOD1/NOD2 interaction and perform the rational drug design.
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CARD Domain of rat RIP2 kinase: Refolding, solution structure, pH-dependent behavior and protein-protein interactions - Fig 1
2018Co-Authors: Sergey A. Goncharuk, Lilya E. Artemieva, Valentin M. Tabakmakher, Alexander S. Arseniev, Konstantin S. MineevAbstract:A - 1H,15N-HSQC spectrum of 300 μM RIP2CARD acquired at pH 4.5, 30°C. Sidechain NH2 groups of Asn and Gln are indicated by thick red lines and folded peaks from the Hε/Nε groups of Arg are marked by asterisks. The assignment is shown on the spectrum, peaks from the polyhistidine tag (MHHHHHHGSGSGLVPRGS) have numbers 1–18. B—The effective rotational correlation times of RIP2CARD N-H vectors, measured based on the cross-correlated relaxation rates.
Jean-luc Poyet - One of the best experts on this subject based on the ideXlab platform.
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the pyrin CARD protein asc is an activating adaptor for caspase 1
Journal of Biological Chemistry, 2002Co-Authors: Srinivasa M Srinivasula, Jean-luc Poyet, Marjaneh Razmara, Pinaki Datta, Zhijia Zhang, Emad S AlnemriAbstract:The PYRIN and CARD Domains are members of the six-helix bundle death Domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN Domain, with procaspase-1 induced activation of procaspase-1 and processing of pro-interleukin-1beta in transfected cells. Substitution of the PYRIN Domain of ASC with an inducible FKBP12 oligomerization Domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN Domain functions as an oligomerization Domain, whereas the CARD Domain functions as the effector Domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1beta generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.
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CARD 8 protein a new CARD family member that regulates caspase 1 activation and apoptosis
Journal of Biological Chemistry, 2002Co-Authors: Marjaneh Razmara, Jean-luc Poyet, John Bertin, Peter S Distefano, Lin Wang, Srinivasa M Srinivasula, Brad J Geddes, Emad S AlnemriAbstract:Caspase-associated recruitment Domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFκB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD Domain with high similarity to the CARD Domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1β generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD Domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-κB activation by TNF-α stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-κB activation.
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CARD10 is a novel caspase recruitment Domain membrane associated guanylate kinase family member that interacts with bcl10 and activates nf κb
Journal of Biological Chemistry, 2001Co-Authors: Lin Wang, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Emad S Alnemri, Yin Guo, Waanjeng Huang, Gulam A Manji, Alexandra M Glucksmann, John BertinAbstract:Abstract BCL10 belongs to the caspase recruitment Domain (CARD) family of proteins that regulate apoptosis and NF-κB signaling pathways. Analysis of BCL10-deficient mice has revealed that BCL10 mediates NF-κB activation by antigen receptors in B and T cells. We recently identified a subclass of CARD proteins (CARD9, CARD11, and CARD14) that may function to connect BCL10 to multiple upstream signaling pathways. We report here that CARD10 is a novel BCL10 interactor that belongs to the membrane-associated guanylate kinase family, a class of proteins that function to organize signaling complexes at plasma membranes. When expressed in cells, CARD10 binds to BCL10 and signals the activation of NF-κB through its N-terminal effector CARD Domain. We propose that CARD10 functions as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-κB.
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CARD11 and CARD14 Are Novel Caspase Recruitment Domain (CARD)/Membrane-associated Guanylate Kinase (MAGUK) Family Members that Interact with BCL10 and Activate NF-κB
Journal of Biological Chemistry, 2001Co-Authors: John Bertin, Jean-luc Poyet, Sarah Merriam, Peter S Distefano, Michael D. Jacobson, Lin Wang, Emad S AlnemriAbstract:Abstract The caspase recruitment Domain (CARD) is a protein-binding module that mediates the assembly of CARD-containing proteins into apoptosis and NF-κB signaling complexes. We report here that CARD protein 11 (CARD11) and CARD protein 14 (CARD14) are novel CARD-containing proteins that belong to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. CARD11 and CARD14 have homologous structures consisting of an N-terminal CARD Domain, a central coiled-coil Domain, and a C-terminal tripartite Domain comprised of a PDZ Domain, an Src homology 3 Domain, and a GUK Domain with homology to guanylate kinase. The CARD Domains of both CARD11 and CARD14 associate specifically with the CARD Domain of BCL10, a signaling protein that activates NF-κB through the IκB kinase complex in response to upstream stimuli. When expressed in cells, CARD11 and CARD14 activate NF-κB and induce the phosphorylation of BCL10. These findings suggest that CARD11 and CARD14 are novel MAGUK family members that function as upstream activators of BCL10 and NF-κB signaling.