Bcl-2-Associated X Protein

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Evripidis Gavathiotis - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic antibodies inhibit Bcl-2-Associated X Protein (BAX) through blockade of the N-terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, David Lee, Jonathan R. Lai, Nikolaos Biris, Sachdev S Sidhu, Zhou Dai, Sheng Li, Evripidis Gavathiotis
    Abstract:

    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolicBAXis activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore.HowtheBAXactivation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1 -α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a bluepr int for developing inhibitors of BAX activation.

  • synthetic antibodies inhibit bcl 2 associated X Protein baX through blockade of the n terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, Nikolaos Biris, Sachdev S Sidhu, Sheng Li, Evripidis Gavathiotis
    Abstract:

    : The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.

  • BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toXic mitochondrial pore
    Trends in Biochemical Sciences, 2011
    Co-Authors: Loren D. Walensky, Evripidis Gavathiotis
    Abstract:

    BAX, the Bcl-2-Associated X Protein, is a cardinal proapoptotic member of the BCL-2 family, which regulates the critical balance between cellular life and death. Because so many medical conditions can be categorized as diseases of either too many or too few cells, dissecting the biochemistry of BCL-2 family Proteins and developing pharmacological strategies to target them have become high priority scientific objectives. Here, we focus on BAX, a latent, cytosolic and monomeric Protein that transforms into a lethal mitochondrial oligomer in response to cellular stress. New insights into the structural location of BAX's ‘on switch', and the multi-step conformational changes that ensue upon BAX activation, are providing fresh opportunities to modulate BAX for potential benefit in human diseases characterized by pathologic cell survival or unwanted cellular demise.

Onyinyechukwu Uchime - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic antibodies inhibit Bcl-2-Associated X Protein (BAX) through blockade of the N-terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, David Lee, Jonathan R. Lai, Nikolaos Biris, Sachdev S Sidhu, Zhou Dai, Sheng Li, Evripidis Gavathiotis
    Abstract:

    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolicBAXis activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore.HowtheBAXactivation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1 -α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a bluepr int for developing inhibitors of BAX activation.

  • synthetic antibodies inhibit bcl 2 associated X Protein baX through blockade of the n terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, Nikolaos Biris, Sachdev S Sidhu, Sheng Li, Evripidis Gavathiotis
    Abstract:

    : The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.

Sheng Li - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic antibodies inhibit Bcl-2-Associated X Protein (BAX) through blockade of the N-terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, David Lee, Jonathan R. Lai, Nikolaos Biris, Sachdev S Sidhu, Zhou Dai, Sheng Li, Evripidis Gavathiotis
    Abstract:

    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolicBAXis activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore.HowtheBAXactivation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1 -α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a bluepr int for developing inhibitors of BAX activation.

  • synthetic antibodies inhibit bcl 2 associated X Protein baX through blockade of the n terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, Nikolaos Biris, Sachdev S Sidhu, Sheng Li, Evripidis Gavathiotis
    Abstract:

    : The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.

Nikolaos Biris - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic antibodies inhibit Bcl-2-Associated X Protein (BAX) through blockade of the N-terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, David Lee, Jonathan R. Lai, Nikolaos Biris, Sachdev S Sidhu, Zhou Dai, Sheng Li, Evripidis Gavathiotis
    Abstract:

    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolicBAXis activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore.HowtheBAXactivation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1 -α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a bluepr int for developing inhibitors of BAX activation.

  • synthetic antibodies inhibit bcl 2 associated X Protein baX through blockade of the n terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, Nikolaos Biris, Sachdev S Sidhu, Sheng Li, Evripidis Gavathiotis
    Abstract:

    : The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.

Sachdev S Sidhu - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic antibodies inhibit Bcl-2-Associated X Protein (BAX) through blockade of the N-terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, David Lee, Jonathan R. Lai, Nikolaos Biris, Sachdev S Sidhu, Zhou Dai, Sheng Li, Evripidis Gavathiotis
    Abstract:

    © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolicBAXis activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore.HowtheBAXactivation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1 -α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a bluepr int for developing inhibitors of BAX activation.

  • synthetic antibodies inhibit bcl 2 associated X Protein baX through blockade of the n terminal activation site
    Journal of Biological Chemistry, 2016
    Co-Authors: Onyinyechukwu Uchime, Nikolaos Biris, Sachdev S Sidhu, Sheng Li, Evripidis Gavathiotis
    Abstract:

    : The BCL-2 Protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-Associated X Protein (BAX) is an eXecutioner Protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toXic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only Protein tBID (truncated Bcl2 interacting Protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium eXchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable compleX without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.