Journal articles on the topic 'Peptide loading'
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1
Liu, Bai, Lijing You, Kaiping Han, Hyung-il Lee, Peter Rhode, Sarah Henrickson, Ulrich H. von Andrian, and Hing C. Wong. "Peptide-loading enhancement for antigen presenting cells (93.6)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S167. http://dx.doi.org/10.4049/jimmunol.178.supp.93.6.
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Abstract Exogenous β2-microglobulin has been shown to enhance the loading of antigenic peptides into MHC class I complexes of antigen presenting cells (APCs). In this study, we employed the multimeric soluble singe-chain T cell receptors and flow cytometry analysis to confirm the activity of exogenous β2 -microglobulin in enhancing the loading of various peptides onto APCs. To our surprise, we found that the enhancement of peptide loading on APCs was restricted to a fraction of the peptides tested. However, a chemical component, commonly used in biological research, exhibits similar peptide loading enhancement activity as that of exogenous β2-microglobulin. The peptide loading enhancement profiles of exogenous β2-microglobulin and the chemical are different and seem to be peptide-dependent. Although the underling mechanism of the chemical for peptide loading enhancement is unknown, the chemical is also found to significantly enhance the endogenous peptide presentation of the gp33 protein of lymphocytic choriomeningitis virus in 5T33 mouse myeloma cells. Thus, a mixture of β2-microglobulin and the chemical could have broad utility in increasing antigen presentation in a variety of experimental applications including vaccine-based approaches.
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Zernich, Danielle, Anthony W. Purcell, Whitney A. Macdonald, Lars Kjer-Nielsen, Lauren K. Ely, Nihay Laham, Tanya Crockford, et al. "Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion." Journal of Experimental Medicine 200, no. 1 (June 28, 2004): 13–24. http://dx.doi.org/10.1084/jem.20031680.
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HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.
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Morozov, Giora I., Huaying Zhao, Michael G. Mage, Lisa F. Boyd, Jiansheng Jiang, Michael A. Dolan, Ramesh Venna, et al. "Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing." Proceedings of the National Academy of Sciences 113, no. 8 (February 11, 2016): E1006—E1015. http://dx.doi.org/10.1073/pnas.1519894113.
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Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8+ T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing.
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Vatner, Ralph Eric, and Pramod K. Srivastava. "The TCP-1 Ring Complex (TRiC) binds antigenic peptides and facilitates their cross-presentation by APCs (93.5)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S166. http://dx.doi.org/10.4049/jimmunol.178.supp.93.5.
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Abstract The multimeric chaperonin TCP-1 Ring Complex (TRiC), an hsp60 homologue, was recently found to associate with the precursors of the ovalbumin-derived SIINFEKL epitope during processing and loading onto MHC I. The TRiC-peptide association is essential for loading of MHC I. Here, we have sought to characterize the peptide-binding properties of TRiC in vitro, and study the behavior of TRiC-peptide complexes in cross-presentation assays. TRiC is shown to bind a variety of peptides in vitro in much the same manner as previously described peptide chaperones of the hsp90 family. TRiC-peptide complexes are efficiently taken up by APCs and the peptides are processed and represented on MHC class I for recognition by specific CD8+ T cells. These results as well as the immunological properties of TRiC-peptide complexes formed in vivo shall be reported.
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Hafstrand, Ida, Ece Canan Sayitoglu, Anca Apavaloaei, Benjamin John Josey, Renhua Sun, Xiao Han, Sara Pellegrino, et al. "Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin." Proceedings of the National Academy of Sciences 116, no. 11 (February 26, 2019): 5055–60. http://dx.doi.org/10.1073/pnas.1807656116.
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MHC-I epitope presentation to CD8+ T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I–bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.
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Badrinath, Soumya, Heike Kunze-Schumacher, Rainer Blasczyk, Trevor Huyton, and Christina Bade-Doeding. "A Micropolymorphism Altering the Residue Triad 97/114/156 Determines the Relative Levels of Tapasin Independence and Distinct Peptide Profiles for HLA-A*24 Allotypes." Journal of Immunology Research 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/298145.
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While many HLA class I molecules interact directly with the peptide loading complex (PLC) for conventional loading of peptides certain class I molecules are able to present peptides in a way that circumvents the PLC components. We investigated micropolymorphisms at position 156 of HLA-A*24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA-A*24:06156Trpand HLA-A*24:13156Leushowed high levels of cell surface expression while HLA-A*24:02156Glnwas expressed at low levels in tapasin deficient cells. Peptides presented by these allelic variants showed distinct differences in features and repertoire. Immunoprecipitation experiments demonstrated all the HLA-A*24/156 variants to associate at similar levels with tapasin when present. Structurally, HLA-A*24:02 contains the residue triad Met97/His114/Gln156 and a Trp156 or Leu156 polymorphism provides tapasin independence by stabilizing these triad residues, thus generating an energetically stable and a more peptide receptive environment. Micropolymorphisms at position 156 can influence the generic peptide loading pathway for HLA-A*24 by altering their tapasin dependence for peptide selection. The trade-off for this tapasin independence could be the presentation of unusual ligands by these alleles, imposing significant risk following hematopoietic stem cell transplantation (HSCT).
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Yuan, Xin, Yingzhou Qin, Qingmei Tian, Cuijuan Liu, Xiangzhou Meng, Bo Qie, Fan Gao, et al. "Smart delivery of poly-peptide composite for effective cancer therapy." Biomedical Materials 17, no. 2 (January 24, 2022): 024103. http://dx.doi.org/10.1088/1748-605x/ac494c.
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Abstract In the past decade, multifunctional peptides have attracted increasing attention in the biomedical field. Peptides possess many impressive advantages, such as high penetration ability, low cost, and etc. However, the short half-life and instability of peptides limit their application. In this study, a poly-peptide drug loading system (called HKMA composite) was designed based on the different functionalities of four peptides. The peptide compositions of HKMA composite from N-terminal to C-terminal were HCBP1, KLA, matrix metalloproteinase-2 (MMP-2)-cleavable peptide and albumin-binding domain. The targeting and lethality of HKMA to NSCLC cell line H460 sphere cells and the half-life of the system were measured in vivo. The results showed that the HKMA composite had a long half-life and specific killing effect on H460 sphere cells in vitro and in vivo. Our result proposed smart peptide drug loading system and provided a potential methodology for effective cancer treatment.
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Ilca, F. Tudor, Andreas Neerincx, Mark R. Wills, Maike de la Roche, and Louise H. Boyle. "Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules." Proceedings of the National Academy of Sciences 115, no. 40 (September 13, 2018): E9353—E9361. http://dx.doi.org/10.1073/pnas.1809465115.
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The repertoire of peptides displayed at the cell surface by MHC I molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-γ secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future.
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Sette, A., S. Southwood, J. Miller, and E. Appella. "Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II." Journal of Experimental Medicine 181, no. 2 (February 1, 1995): 677–83. http://dx.doi.org/10.1084/jem.181.2.677.
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Major histocompatibility complex class II-associated invariant chain (Ii) provides several important functions that regulate class II expression and function. One of these is the ability to inhibit class II peptide loading early in biosynthesis. This allows for efficient class II folding and egress from the endoplasmic reticulum, and protects the class II peptide binding site from loading with peptides before entry into endosomal compartments. The ability of Ii to interact with class II and interfere with peptide loading has been mapped to Ii exon 3, which encodes amino acids 82-107. This same region of Ii has been described as a nested set of class II-associated Ii peptides (CLIPs) that are transiently associated with class II in normal cells and accumulate in human histocompatibility leukocyte antigen-DM-negative cell lines. Currently it is not clear how CLIP and the CLIP region of Ii blocks peptide binding. CLIP may bind directly to the class II peptide binding site, or may bind elsewhere on class II and modulate class II peptide binding allosterically. In this report, we show that CLIP can interact with many different murine and human class II molecules, but that the affinity of this interaction is controlled by polymorphic residues in the class II chains. Likewise, structural changes in CLIP also modulate class II binding in an allele-dependent manner. Finally, the specificity and kinetics of CLIP binding to class II molecule is similar to antigenic peptide binding to class II. These data indicate that CLIP binds to class II in an analogous fashion as conventional antigenic peptides, suggesting that the CLIP segment of Ii may actually occupy the class II peptide binding site.
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Bednarek, M. A., S. Y. Sauma, M. C. Gammon, G. Porter, S. Tamhankar, A. R. Williamson, and H. J. Zweerink. "The minimum peptide epitope from the influenza virus matrix protein. Extra and intracellular loading of HLA-A2." Journal of Immunology 147, no. 12 (December 15, 1991): 4047–53. http://dx.doi.org/10.4049/jimmunol.147.12.4047.
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Abstract Influenza virus matrix protein-derived peptides were synthesized based on the amino acid motifs for HLA-A2 bound self peptides. Among these peptides a nonamer (amino acids 58 through 66: G I L G F V F T L) was found to be 100 to 1000 times more effective than the commonly used peptide 57-68 (K G I L G F V F T L T V) in sensitizing HLA-A2+ target cells to lysis by influenza virus specific cytotoxic T lymphocytes. The sensitizing activity of the 12-mer 57-68 was not due to contamination with shorter and more active peptides. Intracellular expression of peptide 58-66 (mediated by a stable expression plasmid with DNA coding for this peptide) also sensitized HLA-A2+ cells to lysis. Peptide 58-66 stimulated human PBMC to generate CTL that recognized peptides 58-66 and 57-68 in association with HLA-A2.
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Silva-Flannery, Luciana M., Monica Cabrera-Mora, Megan Dickherber, and Alberto Moreno. "Polymeric Linear Peptide Chimeric Vaccine-Induced Antimalaria Immunity Is Associated with Enhanced In Vitro Antigen Loading." Infection and Immunity 77, no. 5 (February 23, 2009): 1798–806. http://dx.doi.org/10.1128/iai.00470-08.
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ABSTRACT Immunization of mice with Plasmodium berghei or Plasmodium yoelii synthetic linear peptide chimeras (LPCs) based on the circumsporozoite protein protects against experimental challenge with viable sporozoites. The immunogenicity of LPCs is significantly enhanced by spontaneous polymerization. To better understand the antigenic properties of polymeric antimalarial peptides, we studied the immune responses elicited in mice immunized with a polymer or a monomer of a linear peptide construct specific for P. yoelii and compared the responses of antigen-presenting cells following incubation with both peptide species. Efficient uptake of the polymeric peptide in vitro resulted in higher expression of the coactivation markers CD80, CD40, and CD70 on dendritic cells and higher proinflammatory cytokine production than with the monomeric peptide. Macropinocytosis seems to be the main route used by polymeric peptides internalized by antigen-presenting cells. Spontaneous polymerization of synthetic antimalarial-peptide constructs to target professional antigen-presenting cells shows promise for simple delivery of subunit malaria vaccines.
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Shi, Guo-Ping, Rebecca A. R. Bryant, Richard Riese, Steven Verhelst, Christoph Driessen, Zhenqiang Li, Dieter Bromme, Hidde L. Ploegh, and Harold A. Chapman. "Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages." Journal of Experimental Medicine 191, no. 7 (April 3, 2000): 1177–86. http://dx.doi.org/10.1084/jem.191.7.1177.
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The major histocompatibility complex (MHC) class II–associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules. Such loading occurs after endosomal degradation of the invariant chain to a ∼3-kD peptide termed CLIP (class II–associated invariant chain peptide). Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s). Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Recombinant cathepsin Z did not generate CLIP from Ii–MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading.
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Natarajan, Kannan, Jiansheng Jiang, Lisa F. Boyd, Giora I. Morozov, Michael G. Mage, and David H. Margulies. "Insights into MHC-I peptide loading obtained from the structure of a TAPBPR/MHC-I complex." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 146.25. http://dx.doi.org/10.4049/jimmunol.198.supp.146.25.
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Abstract The cell surface expression of MHC-I molecules displaying peptides derived from intracellular proteolytic processing is a critical requirement for T cell-mediated immunity. A complex series of steps, guided by the peptide loading machinery in the endoplasmic reticulum, ensures that only stably folded MHC-I molecules carrying peptides of proper length and high affinity are transported for display at the cell surface. TAP-binding protein, related (TAPBPR), has been recently shown to directly bind to certain MHC-I alleles and to facilitate peptide loading. To elucidate mechanistic details, we have examined the binding interaction between purified recombinant TAPBPR and MHC-I molecules loaded with truncated peptides that leave a portion of the peptide binding groove unoccupied. Such MHC-I molecules interact with TAPBPR with nanomolar affinities as measured by surface plasmon resonance and these TAPBPR/MHC-I complexes dissociate when offered a high affinity peptide. An extensive crystallization screen with purified TAPBPR/MHC-I complexes yielded crystals that diffracted to 3.5 Å. The structure of the TAPBPR/MHC-I complex, solved by molecular replacement, and refined at this resolution readily reveals the binding footprint and further structural details of the interaction. Data will be presented on the binding interaction and structural characterization of the TAPBPR/MHC-I complex that reveal insights into the mechanism of TAPBPR- and tapasin-mediated loading of peptides onto MHC-I molecules. (KN and JJ contributed equally to this work).
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Morozov, Giora, Huaying Zhao, Michael Mage, Lisa Boyd, Ramesh Venna, Michael Norcross, Curtis McMurtrey, et al. "Direct interaction of recombinant TAPBPR with MHC-I molecules: stabilization of peptide-free MHC-I promotes high affinity peptide loading (APP5P.102)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 183.4. http://dx.doi.org/10.4049/jimmunol.194.supp.183.4.
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Abstract The loading of MHC-I molecules with peptides for cell surface display is a crucial step in self-tolerance and activation of CD8 T cells. We studied TAPBPR (TAP binding protein-related) protein, a tapasin homolog, which is widely expressed and IFN-γ inducible, but is not part of the classical MHC-I peptide-loading complex. We produced recombinant soluble TAPBPR and evaluated its interactions with several recombinant MHC-I molecules in vitro, by gel-shift, size exclusion chromatography, ultracentrifugation, and surface plasmon resonance. We show that TAPBPR binds MHC-I after photolysis of a bound peptide, and that the TAPBPR/MHC-I complex is dissociated by exposure to peptides that bind the MHC-I molecule, indicating a role of TAPBPR in stabilizing a peptide-receptive form of the MHC-I/β2m complex. Peptide-dependent release of MHC-I from TAPBPR is directly proportional to the peptide’s affinity for MHC-I. Peptide binding experiments indicate a role for TAPBPR in selection of high affinity peptides. Mutagenesis of TAPBPR and MHC-I confirm the importance of amino acid residues conserved with the putative tapasin/MHC-I binding site and reveal additional residues important for the TAPBPR/MHC-I interaction. Molecular docking simulations suggest a detailed mechanism for the interaction of TAPBPR with peptide free MHC-I. These studies are consistent with the view that TAPBPR functions as a chaperone that stabilizes peptide-free MHC-I to permit binding of high affinity peptides.
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Obuobi, Sybil, Venkatesh Mayandi, Nurul Azlyn Mohd Nor, Benedict Jiasheng Lee, Rajamani Lakshminarayanan, and Pui Lai Rachel Ee. "Nucleic acid peptide nanogels for the treatment of bacterial keratitis." Nanoscale 12, no. 33 (2020): 17411–25. http://dx.doi.org/10.1039/d0nr03095c.
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Suh, Woong-Kyung, Michael A. Derby, Myrna F. Cohen-Doyle, Gary J. Schoenhals, Klaus Früh, Jay A. Berzofsky, and David B. Williams. "Interaction of Murine MHC Class I Molecules with Tapasin and TAP Enhances Peptide Loading and Involves the Heavy Chain α3 Domain." Journal of Immunology 162, no. 3 (February 1, 1999): 1530–40. http://dx.doi.org/10.4049/jimmunol.162.3.1530.
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Abstract In human cells the association of MHC class I molecules with TAP is thought to be mediated by a third protein termed tapasin. We now show that tapasin is present in murine TAP-class I complexes as well. Furthermore, we demonstrate that a mutant H-2Dd molecule that does not interact with TAP due to a Glu to Lys mutation at residue 222 of the H chain (Dd(E222K)) also fails to bind to tapasin. This finding supports the view that tapasin bridges the association between class I and TAP and implicates residue 222 as a site of contact with tapasin. The inability of Dd(E222K) to interact with tapasin and TAP results in impaired peptide loading within the endoplasmic reticulum. However, significant acquisition of peptides can still be detected as assessed by the decay kinetics of cell surface Dd(E222K) molecules and by the finding that prolonged viral infection accumulates sufficient target structures to stimulate T cells at 50% the level observed with wild-type Dd. Thus, although interaction with tapasin and TAP enhances peptide loading, it is not essential. Finally, a cohort of Dd(E222K) molecules decays more rapidly on the cell surface compared with wild-type Dd molecules but much more slowly than peptide-deficient molecules. This suggests that some of the peptides obtained in the absence of an interaction with tapasin and TAP are suboptimal, suggesting a peptide-editing function for tapasin/TAP in addition to their role in enhancing peptide loading.
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Sgourakis, Nikolaos, Andrew C. McShan, Kannan Natarajan, Vlad K. Kumirov, David Flores-Solis, Jiansheng Jiang, Mareike Badstuebner, Evgenii L. Kovrigin, and David H. Margulies. "Chaperone-assisted peptide exchange on MHC-I is driven by a negative allostery release cycle: Implications for a role of peptide-editing Molecular Chaperones in scrutinizing the peptide repertoire." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 99.23. http://dx.doi.org/10.4049/jimmunol.200.supp.99.23.
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Abstract Molecular chaperones TAPBPR (TAP-binding protein related) and tapasin associate with major histocompatibility complex class I (MHC-I) to promote the loading of antigenic peptides through a poorly understood mechanism. Here, we use solution Nuclear Magnetic Resonance (NMR) spectroscopy to probe TAPBPR-induced changes on MHC-I. Dynamic motions present in the empty MHC groove become progressively dampened with increasing peptide occupancy, while allosteric communication between the A- and F-pockets regulates a conformational switch located near the TAPBPR binding site, which is crucial for chaperone release from the complex. Our analysis of NMR data recorded for a range of TAPBPR complexes prepared with both murine H2 and human HLA alleles complements the recent X-ray structures to provide atomic-resolution mechanistic insights into the selection of optimal peptide sequences for the displayed antigen repertoire. In particular, our results show that negative allosteric coupling between the MHC groove and chaperone binding sites allows TAPBPR to proofread MHC molecules containing a range of different peptides. Since the affinity of incoming peptides for the empty groove is greatly reduced in the chaperone complex, (micromolar range, relative to nanomolar for the free MHC), these interactions can provide a mechanism for optimizing the peptide repertoire, where only the highest-affinity peptides can drive chaperone release. Finally, our results suggest that TAPBPR may promote the dissociation of tightly bound peptides from MHC molecules, thereby further scrutinizing the displayed repertoire. These findings imply a similar mechanism for the specificity and editing function of tapasin in the peptide-loading complex.
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Stang, Espen, Carolyn B. Guerra, Miguel Amaya, Yvonne Paterson, Oddmund Bakke, and Elizabeth D. Mellins. "DR/CLIP (Class II-Associated Invariant Chain Peptides) and DR/Peptide Complexes Colocalize in Prelysosomes in Human B Lymphoblastoid Cells." Journal of Immunology 160, no. 10 (May 15, 1998): 4696–707. http://dx.doi.org/10.4049/jimmunol.160.10.4696.
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Abstract In APCs, MHC class II molecules (MHC class II) bind antigenic peptides after HLA-DM mediated removal of CLIP. To characterize intracellular sites of peptide loading in human B lymphoblastoid cell lines, we conducted immunoelectron microscopy studies with Abs recognizing MHC class II associated with CLIP or bound peptide, respectively, together with Abs to HLA-DM and endocytic markers. The distribution of these molecules indicates that peptide binding occurs in compartments with characteristics of normal late endosomes, and in compartments that show characteristics of late endosomes, but are not detectably accessed by endocytosed BSA-gold. The latter compartments may represent or give rise to recycling vesicles that deliver peptide-loaded class II molecules to the cell surface. In addition, we have compared cells in which HLA-DM and HLA-DR interaction is defective with cells in which this interaction is intact, and find that DM/DR interaction is not required for the proper localization of either molecule to peptide-loading compartments.
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Braun, Katharina, Christina M. Stürzel, Frank Kirchhoff, and Mika Lindén. "In Vitro Evaluation of a Peptide-Mesoporous Silica Nanoparticle Drug Release System against HIV-1." Inorganics 8, no. 7 (July 13, 2020): 42. http://dx.doi.org/10.3390/inorganics8070042.
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It has been shown that the optimized VIR-576 derivative of the natural HIV-1 entry inhibitor targeting the viral gp41 fusion peptide is safe and effective in infected individuals. However, high doses of this peptide were required, and stability, as well as delivery, must be improved for clinical application. Here, we examined the loading and release of VIR-576 into/from mesoporous silica nanoparticles (MSNs) in vitro. We found that a moderately high peptide loading of 11.5 wt % could be achieved by adsorption from PBS buffer (pH 7.2), i.e., under mild, fully peptide-compatible conditions. The release rate of peptide into the same buffer was slow and the equilibrium concentration as indicated by the adsorption isotherm could not be reached even within 50 h at the particle concentrations studied. However, a faster release was observed at lower particle concentrations, indicating that partial particle dissolution had a positive influence on peptide release. To determine the antiviral activity of VIR-576-loaded MSNs, TZM-bl indicator cells were exposed to HIV-1 and the infection rates were followed as a function of time and VIR-576 concentration. The inhibitory activity observed for VIR-576 released from the MSNs was virtually identical to that of free VIR-576 at the 48 h time point, indicating that (a) VIR-576 was released in an active form from the MSNs, and (b) the release rate in the presence of serum proteins was clearly higher than that observed under protein-free conditions. These observations are discussed based on competitive peptide/protein adsorption, as well as potential influences of serum proteins on the dissolution-reprecipitation of silica under conditions where the total silica concentration is above the saturation level for dissolved silica. Our results highlight the need for studying drug release kinetics in the presence of serum proteins, in order to allow for a better extrapolation of in vitro data to in vivo conditions. Furthermore, due to the high peptide loadings that can be achieved using MSNs as carriers, such a formulation appears promising for local release applications. For systemic administration, however, peptides with a higher potency would be needed, due to their high molar masses limiting the drug loading in terms of moles per gram carrier.
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Wearsch, Pamela, Wei Zhang, and Peter Cresswell. "Essential glycan-dependent interactions optimize MHC class I peptide loading (100.51)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 100.51. http://dx.doi.org/10.4049/jimmunol.186.supp.100.51.
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Abstract In this study we sought to better understand the role of the glycoprotein quality control machinery in the assembly of MHC (Major Histocompatibility Complex) class I molecules with high-affinity peptides. The lectin-like chaperone calreticulin (CRT) and the thiol oxidoreductase ERp57 participate in the final step of this process as part of the PLC (peptide-loading complex). To investigate the mechanism of peptide loading and roles of individual components, we reconstituted a PLC sub-complex, excluding TAP, from purified, recombinant proteins. The minimal components required for PLC assembly and function in vitro were ERp57 disulfide-linked to the class I-specific chaperone tapasin, CRT, and MHC class I complexes bearing monoglucosylated glycans. Mutations disrupting the interaction of CRT with either ERp57 or the class I glycan completely eliminated tapasin-mediated peptide loading. Using the purified system, we also provide direct evidence for a novel role of UGT1 (UDP-glucose: glycoprotein glucosyltransferase 1) in MHC class I assembly. Recombinant UGT1 preferentially recognized and re-glucosylated class I molecules associated with a suboptimal ligand and allowed PLC re-engagement and peptide exchange. Collectively, the data indicate that the interaction of MHC class I molecules with the PLC is regulated by its N-linked glycan, and that UGT1 contributes to the optimization of the MHC class I peptide repertoire in addition to tapasin.
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Brumeanu, T. D., W. J. Swiggard, R. M. Steinman, C. A. Bona, and H. Zaghouani. "Efficient loading of identical viral peptide onto class II molecules by antigenized immunoglobulin and influenza virus." Journal of Experimental Medicine 178, no. 5 (November 1, 1993): 1795–99. http://dx.doi.org/10.1084/jem.178.5.1795.
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Several prior reports have identified peptides that are naturally associated with major histocompatibility complex (MHC) class II molecules on presenting cells. We have examined the delivery of a peptide from exogenous sources to MHC class II molecules. The peptide derives from the influenza virus hemagglutinin (HA) and activates a CD4+ T cell hybridoma. In functional assays of antigen presentation, this epitope is delivered effectively to T cells either in the context of influenza virus or chimeric immunoglobulin (Ig) molecules (Ig-HA) in which the peptide has replaced the CDR3 loop of the heavy chain. We find that the identical 11-mer peptide can be isolated from mouse MHC class II antigens whether the exogenous source of peptide is free HA peptide, the Ig-HA chimera, or ultraviolet-inactivated PR8 influenza virus. The Ig-HA chimera proves to be the most efficient vehicle for charging class II molecules via the exogenous route. Given the fact that self Igs represent natural long-lived carriers, we suggest that antigenized Igs have considerable potential for peptide delivery to MHC molecules in situ.
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Morozov, Giora, Huaying Zhao, Michael Mage, Lisa Boyd, Peter Schuck, Kannan Natarajan, and David Margulies. "Tapasin-related protein TAPBPR interacts directly with peptide-free MHC-I/β2-microgolbulin complexes (APP3P.101)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 111.2. http://dx.doi.org/10.4049/jimmunol.192.supp.111.2.
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Abstract The molecular mechanism by which MHC-I molecules are loaded with peptides is crucial to fundamental aspects of antigen presentation relating to self-tolerance and CD8 T cell activation. To gain insight into the mechanism of MHC-I peptide loading we have studied human TAPBPR (TAP binding protein-related) protein, which is 22% identical to tapasin in amino acid sequence, widely expressed and IFN-γ inducible, but is not part of the peptide-loading complex (PLC). To understand the interaction of TAPBPR with MHC-I, we produced recombinant soluble TAPBPR and evaluated its interactions with MHC-I/β2m complexes in vitro. Using recombinant MHC-I molecules refolded with photolabile peptides, we show, by gel-shift analysis, size exclusion chromatography, and analytical ultracentrifugation that TAPBPR binds MHC-I/β2m after photolysis of the bound peptide, in a 1:1 molar ratio. MHC-I molecules loaded with low-affinity peptides also bind TAPBPR. The TAPBPR/MHC interaction is reversed by exposure to high-affinity peptides known to bind the MHC-I molecule, indicating a role of TAPBPR in stabilizing a peptide-receptive form of the MHC-I/β2m complex. Because of the predicted structural similarity of TAPBPR to tapasin, this system not only provides insight into the molecular details of TAPBPR/MHC-I binding, but may also elucidate tapasin interactions in the PLC that have previously eluded experimental interrogation.
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McCully, Mark, Macarena Sanchez-Navarro, Meritxell Teixido, and Ernest Giralt. "Peptide Mediated Brain Delivery of Nano- and Submicroparticles: A Synergistic Approach." Current Pharmaceutical Design 24, no. 13 (July 11, 2018): 1366–76. http://dx.doi.org/10.2174/1381612824666171201115126.
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The brain is a complex, regulated organ with a highly controlled access mechanism: The Blood-Brain Barrier (BBB). The selectivity of this barrier is a double-edged sword, being both its greatest strength and weakness. This weakness is evident when trying to target therapeutics against diseases within the brain. Diseases such as metastatic brain cancer have extremely poor prognosis due to the poor permeability of many therapeutics across the BBB. Peptides can be designed to target BBB receptors and gain access to the brain by transcytosis. These peptides (known as BBB-shuttles) can carry compounds, usually excluded from the brain, across the BBB. BBB-shuttles are limited by poor loading of therapeutics and degradation of the peptide and cargo. Likewise, nano- submicro- and microparticles can be fine-tuned to limit their degradation and with high loading of therapeutics. However, most nano- and microparticles’ core materials completely lack efficient targeting, with a few selected materials able to cross the BBB passively. Combining the selectivity of peptides with the high loading potential of nano-, microparticles offers an exciting strategy to develop novel, targeted therapeutics towards many brain disorders and diseases. Nevertheless, at present the field is diverse, in both scope and nomenclature, often with competing or contradictory names. In this review, we will try to address some of these issues and evaluate the current state of peptide mediated nano,-microparticle transport to the brain, analyzing delivery vehicle type and peptide design, the two key components that must act synergistically for optimal therapeutic impact.
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Benham, A. M., and J. J. Neefjes. "Proteasome activity limits the assembly of MHC class I molecules after IFN-gamma stimulation." Journal of Immunology 159, no. 12 (December 15, 1997): 5896–904. http://dx.doi.org/10.4049/jimmunol.159.12.5896.
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Abstract For an effective CD8+ cytotoxic T cell response to occur during infection, MHC class I molecules must be loaded with antigenic peptides in the endoplasmic reticulum. The cytosolic factor responsible for peptide generation is believed to be the proteasome, with the TAP heterodimer mediating peptide transport into the endoplasmic reticulum. However, the rate-determining step(s) in this intracellular pathway of Ag presentation is currently unresolved. The availability of a specific and irreversible proteasome inhibitor called lactacystin has enabled us to determine the amount of proteasomes required for the peptide loading of MHC class I molecules in four cell types. In the absence of the IFN-gamma-inducible proteasome subunits LMP2 and LMP7, the trypsin-like (but not the chymotrypsin-like) activity of the proteasome is directly related to MHC class I peptide loading. However, IFN-gamma stimulation or assimilation of catalytic LMP2 and LMP7 subunits into proteasomes causes both chymotrypsin- and trypsin-like activities of the proteasome to become limiting for the loading of class I molecules. Our data suggest that upon full IFN-gamma stimulation, peptide supply by the proteasome is the limiting step in the assembly of MHC class I polypeptides. This mechanism may enable the cell to prevent competition between novel Ags and the pool of endogenous proteins for binding to MHC class I molecules.
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Jiang, Jiansheng, Kannan Natarajan, Ellen Kim, Javeed A. Dhobi, Michael G. Mage, Lisa F. Boyd, and David H. Margulies. "Structural Insights into the Mechanism(s) of Peptide Loading in MHC-I dependent Antigen Presentation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 140.9. http://dx.doi.org/10.4049/jimmunol.204.supp.140.9.
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Abstract Class I MHC molecules (MHC-I) provide crucial cell surface elements that signal health or status of cells for recognition by T cells via their T cell receptor or natural killer (NK) cells via various NK receptors. MHC-I dependent antigen presentation thus influences TCR and NK recognition in immunity to infection, in cancer, and in autoimmunity. Antigen presentation in the MHC-I-dependent pathway depends, in part, on the loading of peptides, derived from proteolysis, aberrant translation, or protein splicing onto MHC-I molecules in the endoplasmic reticulum (ER). The classical pathway of peptide loading and exchange involves components of the peptide loading complex (PLC): the transporter TAP1/2; a lectin, calreticulin; an oxidoreductase, ERp57; a chaperone, tapasin; as well as the peptide-receptive MHC-I molecule and its light chain, b2-microglobulin (b2m). To understand the mechanism of peptide loading and exchange, several laboratories have explored functional and structural aspects of MHC-I interactions with a tapasin homolog, TAP binding protein, related (TAPBPR). We previously reported the structure of a TAPBPR/MHC-I complex at 3.4 Å resolution. However, details of the direct interaction of tapasin with MHC-I are more desirable. Here we report the X-ray crystal structure of tapasin/MHC-I complexes at higher resolution. We discuss similarities and differences between the tapasin/MHC-I and TAPBPR/MHC-I interactions and their implications for MHC-I dependent T cell and NK cell recognition.
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De Luca, Maria, Rosa Gaglione, Bartolomeo Della Ventura, Angela Cesaro, Rocco Di Girolamo, Raffaele Velotta, and Angela Arciello. "Loading of Polydimethylsiloxane with a Human ApoB-Derived Antimicrobial Peptide to Prevent Bacterial Infections." International Journal of Molecular Sciences 23, no. 9 (May 7, 2022): 5219. http://dx.doi.org/10.3390/ijms23095219.
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Background: medical device-induced infections affect millions of lives worldwide and innovative preventive strategies are urgently required. Antimicrobial peptides (AMPs) appear as ideal candidates to efficiently functionalize medical devices surfaces and prevent bacterial infections. In this scenario, here, we produced antimicrobial polydimethylsiloxane (PDMS) by loading this polymer with an antimicrobial peptide identified in human apolipoprotein B, r(P)ApoBLPro. Methods: once obtained loaded PDMS, its structure, anti-infective properties, ability to release the peptide, stability, and biocompatibility were evaluated by FTIR spectroscopy, water contact angle measurements, broth microdilution method, time-killing kinetic assays, quartz crystal microbalance analyses, MTT assays, and scanning electron microscopy analyses. Results: PDMS was loaded with r(P)ApoBLPro peptide which was found to be present not only in the bulk matrix of the polymer but also on its surface. ApoB-derived peptide was found to retain its antimicrobial properties once loaded into PDMS and the antimicrobial material was found to be stable upon storage at 4 °C for a prolonged time interval. A gradual and significant release (70% of the total amount) of the peptide from PDMS was also demonstrated upon 400 min incubation and the antimicrobial material was found to be endowed with anti-adhesive properties and with the ability to prevent biofilm attachment. Furthermore, PDMS loaded with r(P)ApoBLPro peptide was found not to affect the viability of eukaryotic cells. Conclusions: an easy procedure to functionalize PDMS with r(P)ApoBLPro peptide has been here developed and the obtained functionalized material has been found to be stable, antimicrobial, and biocompatible.
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Mage, Michael, Rui Wang, Lisa Boyd, Maria Revilleza, Kannan Natarajan, Ted Hansen, and David Margulies. "Conformation and solvent-accessibility of an MHC-I alpha-1 domain segment provide insight into the peptide receptive transition state (100.6)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 100.6. http://dx.doi.org/10.4049/jimmunol.186.supp.100.6.
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Abstract MHC class I (MHC-I) molecules bound to antigenic peptides form the molecular structures recognized by MHC-I-restricted CD8+ T lymphocytes. On binding an antigenic peptide, the newly synthesized MHC-I sequesters a previously exposed region of the alpha-1 domain including residues 46-52, is released from tapasin, and proceeds to the cell surface. However, the changes in shape of MHC-I on peptide binding and release from tapasin remain unclear. We have determined four X-ray structures (from 1.64Å to 1.87 Å resolution) of an overlapping family of peptides from the H-2Ld alpha-1 domain (including residues 46-52) bound to the Fab fragment of 64-3-7, a mAb that reacts with peptide-receptive (PR) but not with peptide-loaded (PL) H-2Ld MHC-I. Positional differences of backbone and sidechain atoms of this alpha-1 domain segment, compared to the same segment in PL H-2Ld, indicate a significant conformational change on peptide loading. Among other changes, the side chain of the invariant Trp51 residue, and of Met52, although buried in PL MHCI, form extensive noncovalent bonds with mAb 64-3-7, indicating an external (solvent exposed) location in PR MHC-I. Furthermore, the 3(10) helix present in this segment of PL MHC-I is also present in the free peptide bound to MAb 64-3-7, and hence in the PR molecule. These findings help to delineate and provide insight into the conformational changes in MHC-I that accompany peptide loading. Supported by the intramural research program of the NIAID.
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Felt, V. "C-Peptide during Glucose Loading in Myxedema." Hormone and Metabolic Research 20, no. 06 (June 1988): 375. http://dx.doi.org/10.1055/s-2007-1010839.
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Ulbrecht, Matthias, Susanne Modrow, Rakesh Srivastava, Per A. Peterson, and Elisabeth H. Weiss. "Interaction of HLA-E with Peptides and the Peptide Transporter In Vitro: Implications for its Function in Antigen Presentation." Journal of Immunology 160, no. 9 (May 1, 1998): 4375–85. http://dx.doi.org/10.4049/jimmunol.160.9.4375.
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Abstract The assembly of MHC Ia molecules in the endoplasmic reticulum requires the presence of peptide ligands and β2m and is facilitated by chaperones in an ordered sequence of molecular interactions. A crucial step in this process is the interaction of the class I α-chain/β2m dimer with TAP, which is believed to ensure effective peptide loading of the empty class I molecule. We have previously demonstrated impaired intracellular transport of the class Ib molecule HLA-E in mouse myeloma cells cotransfected with the genes for HLA-E and human β2m, which is most likely attributable to inefficient intracellular peptide loading of the HLA-E molecule. We therefore analyzed the ability of HLA-E in the transfectant cell line to bind synthetic peptides by means of their ability to enhance cell surface expression of HLA-E. Peptide binding was confirmed by testing the effect on the thermostability of soluble empty HLA-E/human β2m dimers. Two viral peptides binding to HLA-E were thus identified, for which the exact positioning of the N terminus appeared critical for binding, whereas the contribution of the length of the C terminus seemed to be minor, allowing peptides as short as seven amino acids and up to 16 amino acids to exhibit considerable binding activity. Furthermore, we demonstrate that HLA-E interacts with TAP and that this interaction can be prolonged by the proteasome inhibitor N-acetyl-l-leucyl-l-leucyl-l-norleucinal, which reduces the intracellular peptide pool. The presented data indicate that HLA-E is capable of presenting peptide ligands similar to the repertoire of HLA class Ia molecules.
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Lee, Sungwook, Boyoun Park, Kwonyoon Kang, and Kwangseog Ahn. "Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum." Molecular Biology of the Cell 20, no. 14 (July 15, 2009): 3285–94. http://dx.doi.org/10.1091/mbc.e09-03-0238.
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In contrast to the fairly well-characterized mechanism of assembly of MHC class I-peptide complexes, the disassembly mechanism by which peptide-loaded MHC class I molecules are released from the peptide-loading complex and exit the endoplasmic reticulum (ER) is poorly understood. Optimal peptide binding by MHC class I molecules is assumed to be sufficient for triggering exit of peptide-filled MHC class I molecules from the ER. We now show that protein disulfide isomerase (PDI) controls MHC class I disassembly by regulating dissociation of the tapasin-ERp57 disulfide conjugate. PDI acts as a peptide-dependent molecular switch; in the peptide-bound state, it binds to tapasin and ERp57 and induces dissociation of the tapasin-ERp57 conjugate. In the peptide-free state, PDI is incompetent to bind to tapasin or ERp57 and fails to dissociate the tapasin-ERp57 conjugates, resulting in ER retention of MHC class I molecules. Thus, our results indicate that even after optimal peptide loading, MHC class I disassembly does not occur by default but, rather, is a regulated process involving PDI-mediated interactions within the peptide-loading complex.
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Eggensperger, Sabine, and Robert Tampé. "The transporter associated with antigen processing: a key player in adaptive immunity." Biological Chemistry 396, no. 9-10 (September 1, 2015): 1059–72. http://dx.doi.org/10.1515/hsz-2014-0320.
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Abstract The adaptive immune system co-evolved with sophisticated pathways of antigen processing for efficient clearance of viral infections and malignant transformation. Antigenic peptides are primarily generated by proteasomal degradation and translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides are loaded onto major histocompatibility complex I (MHC I) molecules orchestrated by a multisubunit peptide-loading complex (PLC). Peptide-MHC I complexes are targeted to the cell surface for antigen presentation to cytotoxic T cells, which eventually leads to the elimination of virally infected or malignantly transformed cells. Here, we review MHC I mediated antigen processing with a primary focus on the function and structural organization of the heterodimeric ATP-binding cassette (ABC) transporter TAP1/2. We discuss recent data on the molecular transport mechanism of the antigen translocation complex with respect to structural and biochemical information of other ABC exporters. We further summarize how TAP provides a scaffold for the assembly of the macromolecular PLC, thereby coupling peptide translocation with MHC I loading. TAP inhibition by distinct viral evasins highlights the important role of TAP in adaptive immunity.
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Arshad, Najla, Nathalie Vigneron, Cansu Cimen Bozkus, Vincent Stroobant, Stefan Naulaerts, Nina Bhardwaj, Benoît Van den Eynde, and Peter Cresswell. "Abstract 1379: Discovery of tumor-associated, immunogenic peptides presented in a patient-derived, mutant calreticulin-driven myeloproliferative neoplasm cell line." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1379. http://dx.doi.org/10.1158/1538-7445.am2022-1379.
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Abstract Background: Myeloproliferative neoplasms (MPNs) are a type of chronic blood cancers. A subset are driven by frameshift mutations in the calreticulin gene (CALR). The CALR protein is a lectin chaperone and primarily assists in glycoprotein folding in the endoplasmic reticulum. It is also part of the peptide loading complex, a set of proteins involved in antigen processing and peptide presentation by major histocompatibility complex class I (MHC-I) molecules. All MPN-associated frameshift mutations in CALR lead to a similar change in its C-terminal, altering its protein-protein interactions. Examples include impaired chaperone activity of mutant CALR that impacts protein homeostasis and compromised activity of the MHC-I peptide loading complex. We hypothesized that these impaired functions will alter the repertoire of peptides presented by MHC-I in mutant CALR expressing cells, which we characterized in a patient-derived, mutant-CALR-driven myeloid tumor cell line, Marimo. Methods: We carried out an immunopeptidome analysis on Marimo cell line derivates expressing either wildtype or mutant CALR to identify potential MPN-associated peptides presented by MHC-I, and validated their immunogenicity in human samples. MHC-I-peptide complexes were immunoprecipitated from these Marimo cell line derivates, followed by peptide elution and analysis by mass spectrometry. A subset of peptides that were found in the mass spectrometry analysis of mutant CALR cells but not wildtype CALR cells were tested for their immunogenicity by assaying the in vitro T cell responses they evoked. Naïve T cells from healthy donors, carrying at least one MHC-I allele that matched the Marimo cells, were primed and expanded with the selected peptides and peptide-specific T cell responses were measured by intracellular staining detecting effector cytokines IFN-γ and TNF-α. Results: 1. The expression of mutant CALR disrupts the function of the peptide loading complex, leading to reduced recruitment of MHC-I and reducing its cell surface expression by almost 40% compared to cells expressing wildtype CALR. 2. Peptide repertoire of MHC-I is significantly altered by the expression of mutant CALR. Immunopeptidomics revealed a qualitative and quantitative difference in peptides presented by cells expressing wildtype CALR vs mutant CALR 3. The immunogenicity of a curated list of 24 peptides was tested in healthy donors, and at least 6 peptides activated T cell responses. Similar testing in MPN patients is planned. Conclusions: This is the first study to investigate the impact of mutant CALR on the repertoire of peptides presented by MHC-I in myeloid cells. We discovered tumor-associated, immunogenic peptides that may serve as potential targets of immunotherapy allowing the specific elimination of mutant CALR-expressing cells, which has been a challenge in the treatment of MPNs. Citation Format: Najla Arshad, Nathalie Vigneron, Cansu Cimen Bozkus, Vincent Stroobant, Stefan Naulaerts, Nina Bhardwaj, Benoît Van den Eynde, Peter Cresswell. Discovery of tumor-associated, immunogenic peptides presented in a patient-derived, mutant calreticulin-driven myeloproliferative neoplasm cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1379.
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Ferrari, Giorgio, Andrew M. Knight, Colin Watts, and Jean Pieters. "Distinct Intracellular Compartments Involved in Invariant Chain Degradation and Antigenic Peptide Loading of Major Histocompatibility Complex (MHC) Class II Molecules." Journal of Cell Biology 139, no. 6 (December 15, 1997): 1433–46. http://dx.doi.org/10.1083/jcb.139.6.1433.
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Major histocompatibility complex (MHC) class II molecules are transported to intracellular MHC class II compartments via a transient association with the invariant chain (Ii). After removal of the invariant chain, peptides can be loaded onto class II molecules, a process catalyzed by human leukocyte antigen-DM (HLA-DM) molecules. Here we show that MHC class II compartments consist of two physically and functionally distinct organelles. Newly synthesized MHC class II/Ii complexes were targeted to endocytic organelles lacking HLA-DM molecules, where Ii degradation occurred. From these organelles, class II molecules were transported to a distinct organelle containing HLA-DM, in which peptides were loaded onto class II molecules. This latter organelle was not directly accessible via fluid phase endocytosis, suggesting that it is not part of the endosomal pathway. Uptake via antigen-specific membrane immunoglobulin resulted however in small amounts of antigen in the HLA-DM positive organelles. From this peptide-loading compartment, class II–peptide complexes were transported to the plasma membrane, in part after transit through endocytic organelles. The existence of two separate compartments, one involved in Ii removal and the other functioning in HLA-DM–dependent peptide loading of class II molecules, may contribute to the efficiency of antigen presentation by the selective recruitment of peptide-receptive MHC class II molecules and HLA-DM to the same subcellular location.
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Geng, Jie, Irina Pogozheva, and Malini Raghavan. "Use of functional polymorphisms to elucidate the peptide binding site of the transporter associated with antigen processing (TAP) complexes (APP5P.101)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 183.3. http://dx.doi.org/10.4049/jimmunol.194.supp.183.3.
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Abstract The major histocompatibility (MHC) class I antigen presentation pathway plays an important role in alerting the immune system to virally infected and transformed cells. TAP translocates peptides from the cytosol to the endoplasmic reticulum lumen for peptide loading onto MHC class I molecules. The peptide specificity of TAP has been correlated with the antigenic peptide repertoire of MHC class I molecules in several species, but the precise location of the peptide binding site of TAP is unknown. Polymorphisms in rat and chicken TAPs influence peptide transport selectivity. Combining homology modeling of TAP with experimental measurements of peptide binding selectivity, we demonstrate several residues of rat TAP that are critical for the recognition of basic or hydrophobic residues at the peptide C-terminus, as well as of side chains near the peptide N-terminal and central regions. Based on these interaction sites of peptides with rat TAP, we propose models for rat, chicken and human TAPs in complex with selected peptides. The bound peptides adopt bent conformations and occupy a site near the cytosolic membrane surface, which is similar to that for glutathione derivatives in the NaAtm1 transporter, highlighting conserved elements of bacterial detoxification and eukaryotic immunity-related proteins. These experimentally verified models will facilitate the development of improved epitope discovery tools for assessments of CD8+ T cell prevalence and function in diseases.
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Maharani, Rani, Dessy Yulyani Kurnia, Ace Tatang Hidayat, Jamaludin Al-Anshori, Dadan Sumiarsa, Desi Harneti, and Nurlelasari Nurlelasari. "Upaya Optimasi Sintesis Pentapeptida Leu-Ala-Asn-Ala-Lys dengan Pengurangan Nilai Loading Resin." Chimica et Natura Acta 8, no. 1 (April 15, 2020): 26. http://dx.doi.org/10.24198/cna.v8.n1.28671.
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SCAP1 (Saccostrea Cucullata Antioxidant Peptide 1) dengan urutan asam amino LANAK (Leu-Ala-Asn-Ala-Lys) merupakan pentapeptida yang diisolasi dari hidrolisat tiram dan diketahui memiliki aktivitas antioksidan dengan scavenging radikal DPPH sebesar 83,79 ± 0,53%. Peptida ini telah berhasil dibuat dengan metode sintesis peptida fase padat dengan persen rendemen 8,28%. Rendahnya persen rendemen yang diperoleh disebabkan karena adanya dua residu Ala serta 1 residu Asn yang dapat menyebabkan agregasi. Nilai loading resin yang terlalu besar juga menjadi salah satu penyebab terbentuknya agregasi karena loading resin dilakukan selama 15 jam. Penelitian ini bertujuan untuk menyintesis senyawa SCAP1 dengan pengurangan nilai loading resin. Untuk meningkatkan persen rendemen dari penelitian sebelumnya, pada penelitian ini dilakukan optimasi sintesis terhadap SCAP1. Sintesis dilakukan dengan pengurangan nilai loading resin dengan cara mempersingkat waktu loading resin menjadi 4 jam. Senyawa SCAP1 hasil sintesis memiliki massa crude sebesar 119,5 mg dan berhasil dimurnikan menggunakan RP-HPLC preparatif dengan massa murni 10,6 mg dan rendemen 16%. Penelitian ini menunjukkan bahwa pengurangan loading resin meningkatkan rendemen SCAP1 dari 8,28% menjadi 16%.
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Wu, Ivy, Ryan Park, and Andrew M. Herring. "Combined Electrodialysis and Peptide-Directed Struvite Recovery System." ECS Meeting Abstracts MA2022-02, no. 27 (October 9, 2022): 1041. http://dx.doi.org/10.1149/ma2022-02271041mtgabs.
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Recovery of N and P as struvite (MgNH4PO4 6H2O) has gained interest in recent years as both a flow assurance measure and as a sustainable P source for fertilizer. Electrochemically precipitated struvite offers advantages compared to conventional precipitation methods by reducing the need for expensive additives and has the potential for coupling with renewable energy sources. However, high energy inputs to overcome the solution resistance of most wastewaters limit the feasibility of the technology. In this work, a coupled electrodialysis-struvite recovery system is presented to concentrate the wastewater (producing a separate desalinated stream) while producing struvite in a single unit operation. Furthermore, a common dental peptide was explored as a method to control and increase growth of struvite crystals at neutral pH. Cysteine-capped peptide was attached to a gold mesh substrate in a range of loadings (5-27ug/cm2). Chronoamperometry was conducted by first placing the peptide-loaded mesh in the struvite reactor filled with synthetic wastewater at pH 7.1 and then applying a range of potentials (0.5-0.99V) to the magnesium anode. White precipitates were observed and characterized as struvite by XRD. Struvite crystal morphology was investigated by SEM. We report that a peptide loading of 19 ug/cm2 led to a nearly 14% increase in struvite precipitated compared to bare Au with no peptide attached. Furthermore, longer, dendritic struvite crystals formed in the presence of peptide compared to orthorhombic crystals which formed without peptide. These results indicate that the peptide alters local supersaturation, leading to an increase in directional crystal growth. By demonstrating the utility of peptides for increasing struvite precipitation at neutral pH, our findings improve the viability of electrochemical struvite precipitation for a wider range of wastewater compositions and highlights how peptides can modulate crystal growth.
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Benham, Adam M., Monique Grommé, and Jacques Neefjes. "Allelic Differences in the Relationship Between Proteasome Activity and MHC Class I Peptide Loading." Journal of Immunology 161, no. 1 (July 1, 1998): 83–89. http://dx.doi.org/10.4049/jimmunol.161.1.83.
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Abstract MHC class I molecules are cell surface glycoproteins that play a pivotal role in the response to intracellular pathogens. The loading of MHC class I molecules with antigenic substrates takes place in the endoplasmic reticulum. This requires a functional TAP transporter, which translocates peptides into the endoplasmic reticulum from the cytosol. The generation of antigenic peptides from polypeptide precursors is thought to be mediated in the cytosol by the proteasome. Previously, we have demonstrated that inhibiting the proteasome with the specific covalent inhibitor lactacystin results in a direct reduction of peptide-loaded MHC class I molecules. This indicates that the proteasome is the limiting step in the MHC class I pathway. In this study we use isoelectric focusing to demonstrate that two related MHC class I alleles, HLA-A3 and HLA-A11, as well as HLA-B35 do not follow this behavior. In contrast to other class I alleles expressed by the same cells, these alleles are loaded with peptides and mature normally when proteasome activity is severely inhibited. Our observations highlight a new level of diversity in the MHC class I system and indicate that there are allele-specific differences in the linkage between proteasome activity and MHC class I peptide loading.
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Natarajan, Kannan, Giora Morozov, Jiansheng Jiang, Lisa F. Boyd, Michael G. Mage, and David H. Margulies. "TAPBPR, a Peptide Editor – interactions with MHC complexes and SAXS structural studies." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 116.5. http://dx.doi.org/10.4049/jimmunol.196.supp.116.5.
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Abstract TAPBPR (TAP Binding Protein-Related), a tapasin homolog, functions as a peptide editor independent of the classical peptide loading complex (PLC) that consists of tapasin, transporter associated with antigen processing (TAP), ERp57, and calreticulin. Using insect-cell expressed recombinant luminal human TAPBPR, we previously reported interaction with HLA-A*02:01 molecules freed of peptide following photolysis of HLA-A2/beta2m complexes prepared with photolabile peptides. Here, we extend our analysis of the TABPBPR/MHC interaction by examining the binding of a set of MHC/peptide complexes prepared with different MHC-I molecules refolded with a variety of peptides. Using surface plasmon resonance, we show that a variety of refolded complexes, with or without photolysis of the bound peptide, bind to TAPBPR, raising the possibility that TAPBPR may interact either with a small proportion of peptide free molecules found in some MHC/peptide preparations, or with molecular conformations containing peptide in dynamic equilibrium with the lowest energy state. We extend our analysis of TAPBPR by determination of the low resolution small angle X-ray scattering structures of both TAPBPR and tapasin luminal domains, revealing expected structural similarities.
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Kirschmann, D. A., K. L. Duffin, C. E. Smith, J. K. Welply, S. C. Howard, B. D. Schwartz, and S. L. Woulfe. "Naturally processed peptides from rheumatoid arthritis associated and non-associated HLA-DR alleles." Journal of Immunology 155, no. 12 (December 15, 1995): 5655–62. http://dx.doi.org/10.4049/jimmunol.155.12.5655.
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Abstract Naturally processed peptides from immunoaffinity-purified HLA-DRB1*0401, -DRB1*0404 (rheumatoid arthritis (RA)-associated), and -DRB1*0402 (non-RA-associated) molecules were analyzed by capillary liquid chromatography and mass spectrometry. The molecular weights observed for more than 60 eluted peptides from each HLA-DR protein ranged from 788 to 3535 atomic mass units, corresponding to peptides 7 to 32 amino acids in length. Sequencing of more than 60 of the abundant peptides revealed nested sets of peptides that were derived from only 12 different proteins. The majority of these proteins were membrane-associated (HLA class I, class II, and Ig molecules). Synthetic peptides, corresponding to endogenous peptide sequences, bound with high affinity (5 to 80 nM) to the HLA-DR molecules from which they were eluted. In addition, most were promiscuous binding peptides in that they also bound to other HLA-DR molecules. Truncations of eluted peptide sequences and alanine scanning mutational analysis of a Mycobacterium leprae peptide were used to identify the peptide residues involved in binding to DRB1*0404 and DRB1*0402 molecules. Furthermore, an invariant chain peptide was eluted from the DRB1*0402 molecules but not from the RA-associated molecules. The lack of invariant chain peptides from DRB1*0401 and DRB1*0404 molecules may contribute to the loading of autoantigen peptides into these molecules and to their association with disease.
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Kovats, Susan, Catherine E. Grubin, Susan Eastman, Paul deRoos, Ashok Dongre, Luc Van Kaer, and Alexander Y. Rudensky. "Invariant Chain–independent Function of H-2M in the Formation of Endogenous Peptide–Major Histocompatibility Complex Class II Complexes In Vivo." Journal of Experimental Medicine 187, no. 2 (January 19, 1998): 245–51. http://dx.doi.org/10.1084/jem.187.2.245.
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Efficient loading of major histocompatibility complex class II molecules with peptides requires the invariant chain (Ii) and the class II–like molecule H-2M. Recent in vitro biochemical studies suggest that H2-M may function as a chaperone to rescue empty class II dimers. To test this hypothesis in vivo, we generated mice lacking both Ii and H-2M (Ii−/−M−/−). Antigen presenting cells (APCs) from Ii−/−M−/− mice, as compared with APCs from Ii−/− mice, exhibit a significant reduction in their ability to present self-peptides to a panel of class II I-Ab–restricted T cells. As a consequence of this defect in the loading of self peptides, CD4+ thymocyte development is profoundly impaired in Ii−/−M−/− mice, resulting in a peripheral CD4+ T cell population with low levels of T cell receptor expression. These findings are consistent with the idea that H-2M functions as a chaperone in the peptide loading of class II molecules in vivo.
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Sgourakis, Nikolaos, Andrew C. McShan, Christine A. Devlin, Giora Morozov, and Erik Procko. "Illuminating the Mechanism of MHC-I Folding and Antigen Repertoire Selection Using Deep Mutational Scanning and Biophysical Studies." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 140.21. http://dx.doi.org/10.4049/jimmunol.204.supp.140.21.
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Abstract Chaperones Tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning), and selecting high affinity peptide cargo in the MHC-I groove (editing). While X-ray and cryoEM snapshots of MHC-I molecules prepared in complex with TAPBPR and Tapasin, respectively, have provided important insights into the empty MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Of particular importance is a 16 aa loop region in TAPBPR (corresponding to 11 residues in the sequence of Tapasin), which has been suggested to actively compete with incoming peptides by forming direct contacts with the F-pocket of the empty MHC-I groove. Using a deep mutational scanning functional analysis of TAPBPR, we find that important residues for its chaperoning activity are located on the major interaction surfaces with nascent MHC-I molecules, excluding the loop. However, interactions with properly conformed molecules toward editing of their peptide cargo are influenced by loop mutations, in an MHC-I allele- and peptide-dependent manner, as shown in MHC-I tetramer staining experiments using a TAPBPR library expressed on the surface of yeast. Detailed biophysical characterization by NMR and ITC reveal that the loop does not interact with the empty MHC-I groove to compete with incoming peptides, but instead promotes peptide loading by acting as a kinetic “trap”. Our results suggest that, by utilizing a longer loop, TAPBPR lowers the affinity requirements for peptide selection relative to Tapasin to promote loading under conditions of reduced peptide concentration.
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Amigorena, S., P. Webster, J. Drake, J. Newcomb, P. Cresswell, and I. Mellman. "Invariant chain cleavage and peptide loading in major histocompatibility complex class II vesicles." Journal of Experimental Medicine 181, no. 5 (May 1, 1995): 1729–41. http://dx.doi.org/10.1084/jem.181.5.1729.
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B lymphocytes contain a novel population of endocytic vesicles involved in the transport of newly synthesized major histocompatibility complex (MHC) class II alpha beta chains and alpha beta peptide complexes to the cell surface. We now present evidence that these class II-enriched vesicles (CIIV) are also likely to be a site for the loading of immunogenic peptides onto MHC molecules. We used the serine protease inhibitor leupeptin to accumulate naturally occurring intermediates in the degradation of alpha beta-invariant chain complexes and to slow the intracellular transport of class II molecules. As expected, leupeptin caused an accumulation of Ii chain and class II molecules (I-A(d)) in endosomes and lysosomes. More importantly, however, it enhanced the selective accumulation of a 10-kD invariant chain fragment associated with sodium dodecyl sulfate (SDS)-labile (empty) alpha beta dimers in CIIV. This was followed by the dissociation of the 10-kD fragment, formation of SDS-stable (peptide-loaded) alpha beta dimers, and their subsequent appearance at the cell surface. Thus, CIIV are likely to serve as a specialized site, distinct from endosomes and lysosomes, that hosts the final steps in the dissociation of invariant chain from class II molecules and the loading of antigen-derived peptides onto newly synthesized alpha beta dimers.
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Batista, Patrícia, Pedro M. Castro, Ana Raquel Madureira, Bruno Sarmento, and Manuela Pintado. "Preparation, Characterization and Evaluation of Guar Films Impregnated with Relaxing Peptide Loaded into Chitosan Microparticles." Applied Sciences 11, no. 21 (October 21, 2021): 9849. http://dx.doi.org/10.3390/app11219849.
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Background: Biological molecules such as therapeutic proteins and peptides have provided ample opportunities for further improvements in health and wellbeing. However, such biomacromolecules face stability challenges regarding premature processing and digestion, whenever any enteric delivery route is considered. Hence, oral guar films entrapping peptide-containing chitosan microparticles have been developed as a new delivery system to carry and protect therapeutic relaxing peptides. Results: The composite films were characterized regarding physicochemical properties using FTIR as well as peptide encapsulation efficiency, cytotoxicity, and peptide permeability through buccal and intestinal cell-based models. The composite films with 0.18% (w/w) of peptide demonstrated ca. 0.63% of peptide loading efficiency into the chitosan microparticles and to be safe for buccal and intestinal epithelial cells up to 24 h of contact. The permeability assays through TR146 cells to mimic buccal mucosa epithelium and Caco-2/HT29-MTX to mimic duodenum conditions showed that the incorporation of peptide chitosan microparticles into guar-gum oral films offered a faster permeability, when compared with the free peptide and peptide-chitosan-microparticles-loaded chitosan. Conclusion: This study suggests that peptide-loaded chitosan microparticles into guar-gum oral films might be a promising carrier for enhancement of the buccal and intestinal absorption of a relaxing peptide.
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KARATAŞ, Şule, and Fatma SAVRAN OĞUZ. "MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi." Turkish Journal of Immunology 8, no. 3 (December 2020): 144–56. http://dx.doi.org/10.25002/tji.2020.1364.
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Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription
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Fan, Taotao, Xiaoyan Yu, Bing Shen, and Leming Sun. "Peptide Self-Assembled Nanostructures for Drug Delivery Applications." Journal of Nanomaterials 2017 (2017): 1–16. http://dx.doi.org/10.1155/2017/4562474.
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Peptide self-assembled nanostructures are very popular in many biomedical applications. Drug delivery is one of the most promising applications among them. The tremendous advantages for peptide self-assembled nanostructures include good biocompatibility, low cost, tunable bioactivity, high drug loading capacities, chemical diversity, specific targeting, and stimuli responsive drug delivery at disease sites. Peptide self-assembled nanostructures such as nanoparticles, nanotubes, nanofibers, and hydrogels have been investigated by many researchers for drug delivery applications. In this review, the underlying mechanisms for the self-assembled nanostructures based on peptides with different types and structures are introduced and discussed. Peptide self-assembled nanostructures associated promising drug delivery applications such as anticancer drug and gene drug delivery are highlighted. Furthermore, peptide self-assembled nanostructures for targeted and stimuli responsive drug delivery applications are also reviewed and discussed.
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Rizvi, Syed, and Malini Raghavan. "Tapasin-assisted peptide loading and the nature of the HLA-A2(T134K) assembly defect (106.36)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 106.36. http://dx.doi.org/10.4049/jimmunol.188.supp.106.36.
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Abstract MHC class I molecules are assembled in endoplasmic reticulum (ER) with the help of a peptide loading complex (PLC). The PLC includes specific assembly factors, the transporters associated with antigen processing (TAP) and tapasin, and generic ER chaperones, calreticulin and ERp57. Previous studies have shown that the T134K mutation of HLA-A2 (A2) interferes with cell-surface expression. It has been suggested that reduced cell-surface expression of A2(T134K) is due to impaired interactions of A2(T134K) with tapasin. We expressed the A2(T134K) in a tapasin-deficient cell line (M553), and compared assembly and surface expression of the mutant relative to that of wild-type A2. In M553 cells, the A2(T134K) was profoundly impaired in tapasin-induced cell surface expression. Surprisingly, the A2(T134K) was able to bind to tapasin and TAP. However, compared with A2, assembly of A2(T134K) with β2m was reduced, and ER retention of the mutant was correspondingly enhanced, consistent with impairment in intracellular peptide loading. Similar association kinetics were observed for the interactions of purified empty soluble versions of A2 or A2(T134K) with peptides. On the other hand, both peptide-deficient and peptide-loaded forms of the A2(T134K) were found to be more thermostable compared to wild-type A2. These findings indicate that stabilizing conformational changes induced by the A2(T134K) mutation interfere with tapasin-assisted optimization of the A2(T134K) peptide repertoire.
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Nie, Kun, Xiang Yu, Navnita Kumar, and Yihe Zhang. "Versatile Layer-By-Layer Highly Stable Multilayer Films: Study of the Loading and Release of FITC-Labeled Short Peptide in the Drug Delivery Field." Materials 12, no. 8 (April 12, 2019): 1206. http://dx.doi.org/10.3390/ma12081206.
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A viable short FITC-peptide immobilization is the most essential step in the fabrication of multilayer films based on FITC-peptide. These functional multilayer films have potential applications in drug delivery, medical therapy, and so forth. These FITC-peptides films needed to be handled with a lot of care and precision due to their sensitive nature. In this study, a general immobilization method is reported for the purpose of stabilizing various kinds of peptides at the interfacial regions. Utilizing Mesoporous silica nanoparticles can help in the preservation of these FITC-peptides by embedding themselves into these covalently cross-linked multilayers. This basic outlook of the multilayer films is potent enough and could be reused as a positive substrate. The spatio-temporal retention property of peptides can be modulated by varying the number of capping layers. The release speed of guest molecules such as tyrosine within FITC-peptide or/and adamantane (Ad)-in short peptides could also be fine-tuned by the specific arrangements of the multilayers of mesoporous silica nanoparticles (MSNs) and hyaluronic acid- cyclodextrin (HA-CD) multilayer films.
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Bakker, Jeroen, and Jacques Neefjes. "Identifying MHC class II peptide loading control mechanisms." Molecular Immunology 51, no. 1 (May 2012): 7. http://dx.doi.org/10.1016/j.molimm.2012.02.013.
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Busch, Robert, Robert C. Doebele, Namrata S. Patil, Achal Pashine, and Elizabeth D. Mellins. "Accessory molecules for MHC class II peptide loading." Current Opinion in Immunology 12, no. 1 (February 2000): 99–106. http://dx.doi.org/10.1016/s0952-7915(99)00057-6.
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Bryant, Paula, and Hidde Ploegh. "Class II MHC peptide loading by the professionals." Current Opinion in Immunology 16, no. 1 (February 2004): 96–102. http://dx.doi.org/10.1016/j.coi.2003.11.011.
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