scholarly journals Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin

2019 ◽  
Vol 116 (11) ◽  
pp. 5055-5060 ◽  
Author(s):  
Ida Hafstrand ◽  
Ece Canan Sayitoglu ◽  
Anca Apavaloaei ◽  
Benjamin John Josey ◽  
Renhua Sun ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Molecular Model ◽  
Middle Region ◽  
Mhc I ◽  
Peptide Loading ◽  
Binding Cleft ◽  
Peptide Exchange ◽  
Molecular Bases ◽  
Mutation Analyses ◽  
Selection Of

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.

The transporter associated with antigen processing: a key player in adaptive immunity

2015 ◽  
Vol 396 (9-10) ◽  
pp. 1059-1072 ◽  
Author(s):  
Sabine Eggensperger ◽  
Robert Tampé
Keyword(s):  
Adaptive Immunity ◽  
Antigen Processing ◽  
Viral Infections ◽  
Cytotoxic T Cells ◽  
Adaptive Immune System ◽  
Molecular Transport ◽  
Antigenic Peptides ◽  
Mhc I ◽  
Peptide Loading ◽  
Primary Focus

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.

scholarly journals Association of TAP Gene Polymorphisms and Risk of Cervical Intraepithelial Neoplasia

2013 ◽  
Vol 35 ◽  
pp. 79-84 ◽  
Author(s):  
Camilla Natter ◽  
Stephan Polterauer ◽  
Jasmin Rahhal-Schupp ◽  
Dan Cacsire Castillo-Tong ◽  
Sophie Pils ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Antigen Processing ◽  
Haplotype Analysis ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Genotype Distribution ◽  
Mhc I ◽  
Haplotype Combination ◽  
Significant Difference ◽  
Peptide Loading

Background.Transporter associated with antigen processing (TAP) is responsible for peptide loading onto class I major histocompatibility complex (MHC-I) molecules. TAP seems to facilitate the detection of HPV by MHC-I molecules and contributes to successful eradication of HPV. TAP polymorphisms could have an important impact on the course of HPV infection.Objective.The aim of this study is to evaluate the association between five TAP gene polymorphisms and the risk of CIN.Methods.This case-control study investigated five common TAP polymorphisms in TAP1 (1341 and 2254) and TAP2 (1135, 1693, and 1993) in 616 women with CIN and 206 controls. Associations between gene polymorphisms and risk of CIN were analysed by univariate and multivariable models. The combined effect of the five TAP gene polymorphisms on the risk for CIN was investigated by haplotype analysis.Results.No significant difference in genotype distribution of the five TAP polymorphisms was observed in women with CIN and controls. Haplotype analysis revealed that women with haplotype mut-wt-wt-wt-wt (TAP polymorphisms t1135-t1341-t1693-t1993-t2254) had a significantly lower risk for CIN, compared to women with the haplotype wt-wt-wt-wt-wt (; OR 0.5 []).Conclusion.Identification of this haplotype combination could be used to identify women, less susceptible for development of CIN following HPV infection.

The peptide-loading complex – antigen translocation and MHC class I loading

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Christian Schölz ◽  
Robert Tampé
Keyword(s):  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Display ◽  
Class I ◽  
Antigenic Peptides ◽  
Mhc I ◽  
Protein Fragments ◽  
Long Term Stability ◽  
Peptide Loading ◽  
Mhc Class I Molecules

Abstract A large and dynamic membrane-associated machinery orchestrates the translocation of antigenic peptides into the endoplasmic reticulum (ER) lumen for subsequent loading onto major histocompatibility complex (MHC) class I molecules. The peptide-loading complex ensures that only high-affinity peptides, which guarantee long-term stability of MHC I complexes, are presented to T-lymphocytes. Adaptive immunity is dependent on surface display of the cellular proteome in the form of protein fragments, thus allowing efficient recognition of infected or malignant transformed cells. In this review, we summarize recent findings of antigen translocation by the transporter associated with antigen processing and loading of MHC class I molecules in the ER, focusing on the mechanisms involved in this process.

scholarly journals TAPBPR promotes antigen loading on MHC-I molecules using a peptide trap

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrew C. McShan ◽  
Christine A. Devlin ◽  
Giora I. Morozov ◽  
Sarah A. Overall ◽  
Danai Moschidi ◽  
...  
Keyword(s):  
Amino Acid Sequences ◽  
Mhc I ◽  
Biophysical Characterization ◽  
Specific Amino Acid ◽  
High Affinity ◽  
Loop Sequence ◽  
Peptide Loading ◽  
Groove Structure ◽  
Affinity Peptide ◽  
Selection Of

AbstractChaperones Tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning) and selecting high-affinity peptides in the MHC-I groove (editing). While X-ray and cryo-EM snapshots of MHC-I in complex with TAPBPR and Tapasin, respectively, have provided important insights into the peptide-deficient MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Based on structural and functional data, a loop sequence of variable lengths has been proposed to stabilize empty MHC-I molecules through direct interactions with the floor of the groove. Using deep mutagenesis on two complementary expression systems, we find that important residues for the Tapasin/TAPBPR chaperoning activity are located on a large scaffolding surface, excluding the loop. Conversely, loop mutations influence TAPBPR interactions with properly conformed MHC-I molecules, relevant for peptide editing. Detailed biophysical characterization by solution NMR, ITC and FP-based assays shows that the loop hovers above the MHC-I groove to promote the capture of incoming peptides. Our results suggest that the longer loop of TAPBPR lowers the affinity requirements for peptide selection to facilitate peptide loading under conditions and subcellular compartments of reduced ligand concentration, and to prevent disassembly of high-affinity peptide-MHC-I complexes that are transiently interrogated by TAPBPR during editing.

scholarly journals TAPBPR Promotes Antigen Loading on MHC-I Molecules Using a Peptide Trap

2020 ◽  
Author(s):  
Andrew McShan ◽  
Christine Devlin ◽  
Giora Morozov ◽  
Sarah Overall ◽  
Danai Moschidi ◽  
...  
Keyword(s):  
Amino Acid Sequences ◽  
Mhc I ◽  
Biophysical Characterization ◽  
Specific Amino Acid ◽  
High Affinity ◽  
Loop Sequence ◽  
Peptide Loading ◽  
Groove Structure ◽  
Affinity Peptide ◽  
Selection Of

Abstract Chaperones Tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning) and selecting high affinity peptides in the MHC-I groove (editing). While X-ray and cryo-EM snapshots of MHC-I in complex with TAPBPR and Tapasin, respectively, have provided important insights into the peptide-deficient MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Based on structural and functional data, a loop sequence of variable lengths has been proposed to stabilize empty MHC-I molecules through direct interactions with the floor of the groove. Using deep mutagenesis on two complementary expression systems, we find that important residues for the Tapasin/TAPBPR chaperoning activity are located on a large scaffolding surface, excluding the loop. Conversely, loop mutations influence TAPBPR interactions with properly conformed MHC-I molecules, relevant for peptide editing. Detailed biophysical characterization by solution NMR, ITC and FP-based shows that the loop hovers above the MHC-I groove to promote the capture of incoming peptides, thereby acting as a trap. Our results suggest that the longer loop of TAPBPR lowers the affinity requirements for peptide selection to facilitate peptide loading under conditions and subcellular compartments of reduced ligand concentration, and to prevent disassembly of high affinity peptide-MHC-I complexes that are transiently interrogated by TAPBPR during editing.

The TAP translocation machinery in adaptive immunity and viral escape mechanisms

2011 ◽  
Vol 50 ◽  
pp. 249-264 ◽  
Author(s):  
Rupert Abele ◽  
Robert Tampé
Keyword(s):  
Antigen Processing ◽  
Genetic Diseases ◽  
Adaptive Immune System ◽  
Principal Component ◽  
Viral Escape ◽  
Antigenic Peptides ◽  
Adapter Protein ◽  
Mhc I ◽  
Peptide Loading ◽  
Cellular Machinery

The adaptive immune system plays an essential role in protecting vertebrates against a broad range of pathogens and cancer. The MHC class I-dependent pathway of antigen presentation represents a sophisticated cellular machinery to recognize and eliminate infected or malignantly transformed cells, taking advantage of the proteasomal turnover of the cell's proteome. TAP (transporter associated with antigen processing) 1/2 (ABCB2/3, where ABC is ATP-binding cassette) is the principal component in the recognition, translocation, chaperoning, editing and final loading of antigenic peptides on to MHC I complexes in the ER (endoplasmic reticulum) lumen. These different tasks are co-ordinated within a dynamic macromolecular peptide-loading complex consisting of TAP1/2 and various auxiliary factors, such as the adapter protein tapasin, the oxidoreductase ERp57, the lectin chaperone calreticulin, and the final peptide acceptor the MHC I heavy chain associated with β2-microglobulin. In this chapter, we summarize the structural organization and molecular mechanism of the antigen-translocation machinery as well as various modes of regulation by viral factors and in genetic diseases and tumour development.

The ABCs of Immunology: Structure and Function of TAP, the Transporter Associated with Antigen Processing

Physiology ◽  
2004 ◽  
Vol 19 (4) ◽  
pp. 216-224 ◽  
Author(s):  
Rupert Abele ◽  
Robert Tampé
Keyword(s):  
Antigen Processing ◽  
Cytotoxic T Cells ◽  
Peptide Delivery ◽  
Structure And Function ◽  
Transformed Cells ◽  
Tumor Escape ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
And Function

The transporter associated with antigen processing (TAP) is essential for peptide delivery from the cytosol into the lumen of the endoplasmic reticulum (ER), where these peptides are loaded on major histocompatibility complex (MHC) I molecules. Loaded MHC I leave the ER and display their antigenic cargo on the cell surface to cytotoxic T cells. Subsequently, virus-infected or malignantly transformed cells can be eliminated. Here we discuss the structure, function, and mechanism of TAP as a central part of the peptide-loading complex. Furthermore, aspects of virus and tumor escape strategies are presented.

scholarly journals Light control of the peptide-loading complex synchronizes antigen translocation and MHC I trafficking

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jamina Brunnberg ◽  
Valentina Herbring ◽  
Esteban Günther Castillo ◽  
Heike Krüger ◽  
Ralph Wieneke ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Antigen Processing ◽  
Adaptive Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Atp Binding Site ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Cellular Pathways ◽  
Cancerous Cells

AbstractAntigen presentation via major histocompatibility complex class I (MHC I) molecules is essential to mount an adaptive immune response against pathogens and cancerous cells. To this end, the transporter associated with antigen processing (TAP) delivers snippets of the cellular proteome, resulting from proteasomal degradation, into the ER lumen. After peptide loading and editing by the peptide-loading complex (PLC), stable peptide-MHC I complexes are released for cell surface presentation. Since the process of MHC I trafficking is poorly defined, we established an approach to control antigen presentation by introduction of a photo-caged amino acid in the catalytic ATP-binding site of TAP. By optical control, we initiate TAP-dependent antigen translocation, thus providing new insights into TAP function within the PLC and MHC I trafficking in living cells. Moreover, this versatile approach has the potential to be applied in the study of other cellular pathways controlled by P-loop ATP/GTPases.

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