The Human Transporter Associated with Antigen Processing

Corradi, Valentina; Singh, G.; Tieleman, D. Peter

doi:10.1074/jbc.m112.381251

Cited by 26 publications

(23 citation statements)

References 110 publications

(107 reference statements)

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“…Based on the results described in this study, we constructed three-dimensional models of peptide-TAP complexes for rat, chicken and human TAPs (Figures 8 and S3–S4), which were extensively validated in the context of known experimental data and functional polymorphism of rat and chicken TAPs. Our model of rat TAP in the outward-facing state is similar to previously published Sav1866-based models of the human TAP (22, 37). In contrast, the inward-facing conformation of our TAP complexes significantly differ from previously published human TAP models that were produced based on P-glycoprotein, MsbA, and ABCB10 crystal structures (22).…”

Section: Discussionsupporting

confidence: 67%

“…Our model of rat TAP in the outward-facing state is similar to previously published Sav1866-based models of the human TAP (22, 37). In contrast, the inward-facing conformation of our TAP complexes significantly differ from previously published human TAP models that were produced based on P-glycoprotein, MsbA, and ABCB10 crystal structures (22). …”

Section: Discussionsupporting

confidence: 67%

“…The sequence alignments of the core TMDs of TAPs modeled in this work are present on Figure S1. Sequence alignments of NBD domains have been previously published (22). …”

Section: Methodsmentioning

confidence: 99%

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Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes

Geng

Pogozheva

Mosberg

et al. 2015

The Journal of Immunology

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The transporter associated with antigen processing (TAP) translocates peptides from the cytosol to the endoplasmic reticulum (ER) lumen to enable immune surveillance by CD8+ T cells. Peptide transport is preceded by peptide binding to a cytosol-accessible surface of TAP1/TAP2 complexes, but the location of the TAP peptide-binding pocket remains unknown. Guided by the known contributions of polymorphic TAP variants to peptide selection, we combined homology modeling of TAP with experimental measurements to identify several TAP residues that interact with peptides. Models for peptide-TAP complexes were generated, which indicate bent conformation for peptides. The peptide-binding site of TAP is located at the hydrophobic boundary of the cytosolic membrane leaflet, with striking parallels to the glutathione binding site of NaAtm1, a transporter that functions in bacterial heavy metal detoxification. These studies illustrate the conservation of the ligand recognition modes of bacterial and mammalians transporters involved in peptide-guided cellular surveillance.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 67%

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Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes

Geng

Pogozheva

Mosberg

et al. 2015

The Journal of Immunology

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“…7J), tapasin binding to the coreTMD of TAP1 is almost eliminated. Recently, Corradi and co-workers constructed homology models of the assembled TAP1:TAP2 heterodimer based on published crystal structures from ABC transporters (48). We used two of their models, one based on the inward-facing conformation of ABCB10 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Three Tapasin Docking Sites in TAP Cooperate To Facilitate Transporter Stabilization and Heterodimerization

Leonhardt

Abrahimi

Mitchell

et al. 2014

The Journal of Immunology

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The transporter associated with antigen processing (TAP) translocates peptide antigens into the lumen of the endoplasmic reticulum (ER) for loading onto major histocompatibility complex (MHC) class I molecules. MHC class I acquires its peptide cargo in the peptide loading complex (PLC), an oligomeric complex that the chaperone tapasin organizes by bridging TAP to MHC class I and recruiting accessory molecules such as ERp57 and calreticulin. Three tapasin binding sites on TAP have been described, two of which are located in the N-terminal domains (N domains) of TAP1 and TAP2. The third binding site is present in the core transmembrane domain (coreTMD) of TAP1 and is only used by the unassembled subunits. Tapasin is required to promote TAP stability, but through which binding site(s) it is acting is unknown. In particular the role of tapasin binding to the coreTMD of TAP1 single chains is mysterious as this interaction is lost upon TAP2 association. In this study, we map the respective binding site in TAP1 to the polar face of the amphipathic transmembrane helix TM9 and identify key residues that are essential to establish the interaction. We find that this interaction is dispensable for the peptide transport function but essential to achieve full stability of human TAP1. The interaction is also required for proper heterodimerization of the transporter. Based on similar results obtained using TAP mutants lacking tapasin binding to either N domain, we conclude that all three tapasin-binding sites in TAP cooperate to achieve high transporter stability and efficient heterodimerization.

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“…Since Pgp exhibits a high degree of structural flexibility (22), a more meaningful docking would take advantage of conformation ensembles generated by MD simulations (34, 35). A more rigorous approach has been utilized to model the bound substrate in a different ABC transporter, where the protein-substrate interactions were exhaustively sampled using replica-exchange simulations (36). …”

Section: Dissecting Functionally Relevant Chemical Detailsmentioning

confidence: 99%

Computational characterization of structural dynamics underlying function in active membrane transporters

Wen

Moradi

et al. 2015

Current Opinion in Structural Biology

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Active transport of materials across the cellular membrane is one the most fundamental processes in biology. In order to accomplish this task, membrane transporters rely on a wide range of conformational changes spanning multiple time and size scales. These molecular events govern key functional aspects in membrane transporters, namely, coordinated gating motions underlying the alternating access mode of operation, and coupling of uphill transport of substrate to various sources of energy, e.g., transmembrane electrochemical gradients and ATP binding and hydrolysis. Computational techniques such as molecular dynamics simulations and free energy calculations have equipped us with a powerful repertoire of biophysical tools offering unparalleled spatial and temporal resolutions that can effectively complement experimental methodologies, and therefore help fill the gap of knowledge in understanding the molecular basis of function in membrane transporters.

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The Human Transporter Associated with Antigen Processing

Cited by 26 publications

References 110 publications

Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes

Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes

Three Tapasin Docking Sites in TAP Cooperate To Facilitate Transporter Stabilization and Heterodimerization

Computational characterization of structural dynamics underlying function in active membrane transporters

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