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Srin Sastry - One of the best experts on this subject based on the ideXlab platform.
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identification of the peptide binding site in the heat shock chaperone tumor rejection antigen Gp96 grp94
Journal of Biological Chemistry, 2000Co-Authors: Nora A Linderoth, Anthony Popowicz, Srin SastryAbstract:Abstract Heat shock protein (HSP)-peptide complexes from tumor cells elicit specific protective immunity when injected into inbred mice bearing the same specific type of tumor. The HSP-mediated specific immunogenicity also occurs with virus-infected cells. The immune response is solely due to endogenous peptides noncovalently bound to HSP. A vesicular stomatitis virus capsid-derived peptide ligand bearing a photoreactive azido group was specifically bound by and cross-linked to murine HSP Glycoprotein (Gp) 96. The peptide-binding site was mapped by specific proteolysis of the cross-links followed by analysis of the cross-linked peptides using a judicious combination of SDS-gel electrophoresis, mass spectrometry, and amino acid sequencing. The minimal peptide-binding site was mapped to amino acid residues 624–630 in a highly conserved region of Gp96. A model of the peptide binding pocket of Gp96 was constructed based on the known crystallographic structure of major histocompatibility complex class I molecule bound to a similar peptide. The Gp96-peptide model predicts that the peptide ligand is held in a groove formed by α-helices and lies on a surface consisting of antiparallel β-sheets. Interestingly, in this model, the peptide binding pocket abuts the dimerization domain of Gp96, which may have implications for the extraordinary stability of peptide-Gp96 complexes, and for the faithful relay of peptides to major histocompatibility complex class I molecule for antigen presentation.
Nora A Linderoth - One of the best experts on this subject based on the ideXlab platform.
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identification of the peptide binding site in the heat shock chaperone tumor rejection antigen Gp96 grp94
Journal of Biological Chemistry, 2000Co-Authors: Nora A Linderoth, Anthony Popowicz, Srin SastryAbstract:Abstract Heat shock protein (HSP)-peptide complexes from tumor cells elicit specific protective immunity when injected into inbred mice bearing the same specific type of tumor. The HSP-mediated specific immunogenicity also occurs with virus-infected cells. The immune response is solely due to endogenous peptides noncovalently bound to HSP. A vesicular stomatitis virus capsid-derived peptide ligand bearing a photoreactive azido group was specifically bound by and cross-linked to murine HSP Glycoprotein (Gp) 96. The peptide-binding site was mapped by specific proteolysis of the cross-links followed by analysis of the cross-linked peptides using a judicious combination of SDS-gel electrophoresis, mass spectrometry, and amino acid sequencing. The minimal peptide-binding site was mapped to amino acid residues 624–630 in a highly conserved region of Gp96. A model of the peptide binding pocket of Gp96 was constructed based on the known crystallographic structure of major histocompatibility complex class I molecule bound to a similar peptide. The Gp96-peptide model predicts that the peptide ligand is held in a groove formed by α-helices and lies on a surface consisting of antiparallel β-sheets. Interestingly, in this model, the peptide binding pocket abuts the dimerization domain of Gp96, which may have implications for the extraordinary stability of peptide-Gp96 complexes, and for the faithful relay of peptides to major histocompatibility complex class I molecule for antigen presentation.
Anthony Popowicz - One of the best experts on this subject based on the ideXlab platform.
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identification of the peptide binding site in the heat shock chaperone tumor rejection antigen Gp96 grp94
Journal of Biological Chemistry, 2000Co-Authors: Nora A Linderoth, Anthony Popowicz, Srin SastryAbstract:Abstract Heat shock protein (HSP)-peptide complexes from tumor cells elicit specific protective immunity when injected into inbred mice bearing the same specific type of tumor. The HSP-mediated specific immunogenicity also occurs with virus-infected cells. The immune response is solely due to endogenous peptides noncovalently bound to HSP. A vesicular stomatitis virus capsid-derived peptide ligand bearing a photoreactive azido group was specifically bound by and cross-linked to murine HSP Glycoprotein (Gp) 96. The peptide-binding site was mapped by specific proteolysis of the cross-links followed by analysis of the cross-linked peptides using a judicious combination of SDS-gel electrophoresis, mass spectrometry, and amino acid sequencing. The minimal peptide-binding site was mapped to amino acid residues 624–630 in a highly conserved region of Gp96. A model of the peptide binding pocket of Gp96 was constructed based on the known crystallographic structure of major histocompatibility complex class I molecule bound to a similar peptide. The Gp96-peptide model predicts that the peptide ligand is held in a groove formed by α-helices and lies on a surface consisting of antiparallel β-sheets. Interestingly, in this model, the peptide binding pocket abuts the dimerization domain of Gp96, which may have implications for the extraordinary stability of peptide-Gp96 complexes, and for the faithful relay of peptides to major histocompatibility complex class I molecule for antigen presentation.
Daniele Arnoldschild - One of the best experts on this subject based on the ideXlab platform.
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cross presentation of Glycoprotein 96 associated antigens on major histocompatibility complex class i molecules requires receptor mediated endocytosis
Journal of Experimental Medicine, 2000Co-Authors: Harpreet Singhjasuja, Rene E M Toes, Pieter Spee, Christian Munz, Norbert Hilf, Stephen P Schoenberger, Paola Ricciardicastagnoli, Jacques Neefjes, Hansgeorg Rammensee, Daniele ArnoldschildAbstract:Heat shock proteins (HSPs) like Glycoprotein (Gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by Gp96-chaperoned peptides, specific receptor-mediated uptake of Gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind Gp96. The binding is saturable and can be inhibited using unlabeled Gp96 molecules. Receptor binding by APCs leads to a rapid internalization of Gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of Gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant Gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of Gp96 molecules leads to MHC class I–restricted re-presentation of Gp96-associated peptides and CTL activation; non–receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which Gp96 is participating in the cross-presentation of antigens from cellular origin.
Harpreet Singhjasuja - One of the best experts on this subject based on the ideXlab platform.
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cross presentation of Glycoprotein 96 associated antigens on major histocompatibility complex class i molecules requires receptor mediated endocytosis
Journal of Experimental Medicine, 2000Co-Authors: Harpreet Singhjasuja, Rene E M Toes, Pieter Spee, Christian Munz, Norbert Hilf, Stephen P Schoenberger, Paola Ricciardicastagnoli, Jacques Neefjes, Hansgeorg Rammensee, Daniele ArnoldschildAbstract:Heat shock proteins (HSPs) like Glycoprotein (Gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by Gp96-chaperoned peptides, specific receptor-mediated uptake of Gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind Gp96. The binding is saturable and can be inhibited using unlabeled Gp96 molecules. Receptor binding by APCs leads to a rapid internalization of Gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of Gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant Gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of Gp96 molecules leads to MHC class I–restricted re-presentation of Gp96-associated peptides and CTL activation; non–receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which Gp96 is participating in the cross-presentation of antigens from cellular origin.