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.

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 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.

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 Atomistic structure and dynamics of the human MHC-I peptide-loading complex

2020 ◽  
Vol 117 (34) ◽  
pp. 20597-20606 ◽  
Author(s):  
Olivier Fisette ◽  
Gunnar F. Schröder ◽  
Lars V. Schäfer
Keyword(s):  
Conformational Dynamics ◽  
Water Environment ◽  
Adaptive Immune System ◽  
Md Simulations ◽  
Class I Mhc ◽  
Mhc I ◽  
Active Core ◽  
Peptide Loading ◽  
Catalytically Active ◽  
Binding Groove

The major histocompatibility complex class-I (MHC-I) peptide-loading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.

scholarly journals Physical and Functional Association of the Major Histocompatibility Complex Class I Heavy Chain α3 Domain with the Transporter Associated with Antigen Processing

1998 ◽  
Vol 187 (6) ◽  
pp. 865-874 ◽  
Author(s):  
Kimary Kulig ◽  
Dipankar Nandi ◽  
Igor Bacik ◽  
John J. Monaco ◽  
Stanislav Vukmanovic
Keyword(s):  
Mhc Class Ii ◽  
Heavy Chain ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Antigenic Peptides ◽  
Histocompatibility Complex ◽  
Cytoplasmic Proteins ◽  
Peptide Loading ◽  
Er Targeting

CD8+ T lymphocytes recognize antigens as short, MHC class I-associated peptides derived by processing of cytoplasmic proteins. The transporter associated with antigen processing translocates peptides from the cytosol into the ER lumen, where they bind to the nascent class I molecules. To date, the precise location of the class I-TAP interaction site remains unclear. We provide evidence that this site is contained within the heavy chain α3 domain. Substitution of a 15 amino acid portion of the H-2Db α3 domain (aa 219-233) with the analogous MHC class II (H-2IAd) β2 domain region (aa 133-147) results in loss of surface expression which can be partially restored upon incubation at 26°C in the presence of excess peptide and β2-microglobulin. Mutant H-2Db (Db219-233) associates poorly with the TAP complex, and cannot present endogenously-derived antigenic peptides requiring TAP-dependent translocation to the ER. However, this presentation defect can be overcome through use of an ER targeting sequence which bypasses TAP-dependent peptide translocation. Thus, the α3 domain serves as an important site of interaction (directly or indirectly) with the TAP complex and is necessary for TAP-dependent peptide loading and class I surface expression.

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.

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.

scholarly journals Long-term and short-term immunity to SARS-CoV-2: why it matters

2021 ◽  
Vol 42 (1) ◽  
pp. 34
Author(s):  
John Zaunders ◽  
Chansavath Phetsouphanh
Keyword(s):  
Immune Response ◽  
Adaptive Immunity ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Recurrent Infection ◽  
Adaptive Immune System ◽  
Upper Respiratory Tract ◽  
Short Term ◽  
Adaptive Immune ◽  
Tract Infections

The adaptive immune system, regulated by CD4 T cells, is essential for control of many viral infections. Endemic coronavirus infections generally occur as short-term upper respiratory tract infections which in many cases appear to be cleared before adaptive immunity is fully involved, since adaptive immunity takes approximately 1.5–2 weeks to ramp up the response to a primary infection, or approximately 1 week for a recurrent infection. However, the adaptive immune response to SARS-CoV-2 infection will be critical to full recovery with minimal long-lasting effects, and to either prevention of recurrence of infection or at least reduced severity of symptoms. The detailed kinetics of this infection versus the dynamics of the immune response, including in vaccinated individuals, will largely determine these outcomes.

scholarly journals A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1

2020 ◽  
Vol 295 (21) ◽  
pp. 7193-7210 ◽  
Author(s):  
George Mavridis ◽  
Richa Arya ◽  
Alexander Domnick ◽  
Jerome Zoidakis ◽  
Manousos Makridakis ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Antigen Processing ◽  
Peptide Binding ◽  
Antigenic Peptide ◽  
Antigenic Peptides ◽  
Peptide Loading ◽  
Peptide Precursors ◽  
Peptide Dissociation ◽  
Endoplasmic Reticulum Aminopeptidase 1 ◽  
Computational Analyses

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in preformed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08, and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12-mer progressed at a considerable rate, albeit still slower than in solution. Results from thermodynamic, kinetic, and computational analyses suggested that this 12-mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissociation. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from preformed MHCI complexes as efficiently as ERAP1. A pseudopeptide analogue with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1/MHCI/peptide complex. Similarly, no interactions between ERAP1 and purified peptide-loading complex were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degradation and that trimming in solution along with the dynamic nature of peptide binding to MHCI are sufficient to explain ERAP1 processing of antigenic peptide precursors.

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