An Annular Lipid Belt Is Essential for Allosteric Coupling and Viral Inhibition of the Antigen Translocation Complex TAP (Transporter Associated with Antigen Processing)

Eggensperger, Sabine; Fisette, Olivier; Parcej, David; Schäfer, Lars V.; Tampé, Robert

doi:10.1074/jbc.m114.592832

Cited by 27 publications

(37 citation statements)

References 55 publications

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“…Surprisingly, the active domain alone, which was used to study the TAP function32024, decreased thermostability, while the fused active domain alone led to a slight increase in stability. ICP47 interacts via a large interface with TAP, involving most of the residues of the active domain of ICP4721.…”

Section: Discussionmentioning

confidence: 99%

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A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex

Herbring

Bäucker

Trowitzsch

et al. 2016

Sci Rep

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As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion. The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. Here, we report on a thermostable ICP47-TAP complex, generated by fusion of different ICP47 fragments. These fusion complexes allowed us to determine the direction and positioning in the central cavity of TAP. ICP47-TAP fusion complexes are arrested in a stable conformation, as demonstrated by MHC I surface expression, melting temperature, and the mutual exclusion of herpesviral TAP inhibitors. We unveiled a conserved region next to the active domain of ICP47 as essential for the complete stabilization of the TAP complex. Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. Based on our findings, we propose a dual interaction mechanism for ICP47. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. These new insights into the ICP47 inhibition mechanism can be applied for future structural analyses of the TAP complex.

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Section: Discussionmentioning

confidence: 99%

“…ICP47, also known as IE12, Vmw12, or IE5, binds to TAP from the cytosol ( K D = 50 nM) and arrests its function1516171819. For ICP47 binding, both TAP subunits are required1617, but the TMD0s are dispensable20. The active domain comprises residues 3-34 of ICP47, which displays the same inhibitory activity as the full-length protein1921.…”

mentioning

confidence: 99%

A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex

Herbring

Bäucker

Trowitzsch

et al. 2016

Sci Rep

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“…While, to our knowledge there are only a few reported molecular simulation studies of SMALPS nanodiscs to date (two papers not discussed here are 54,55 ), the field of nanoparticle simulation in general is growing at a rapid rate. Numerous studies of the interaction of fullerenes, carbon nanotubes, and dendrimers with lipid bilayers have been published in the last few years [56][57][58][59][60] .…”

Section: Opportunity For Use In Molecular Simulationmentioning

confidence: 99%

Encapsulated membrane proteins: A simplified system for molecular simulation

Lee¹,

Khalid²,

Pollock³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2Over the past 50 years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modeling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherentlycomplex.An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations.These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics.

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“…As the lipid environment has a strong impact on TAP function, the analysis of the transporter reconstituted in membrane systems became indispensable. The successful insertion of TAP and other ABC transporters into nanodiscs provides new options to study the transport mechanism in a membrane-embedded environment (Kawai et al, 2011;Ritchie et al, 2011;Bao and Duong, 2014;Eggensperger et al, 2014;Nasr and Singh, 2014). For TAP in nanodiscs, an annular lipid belt was found to be sufficient to maintain TAP function .…”

Section: Transport Mechanism For Tapmentioning

confidence: 99%

“…The ability to block peptide binding is restricted to human TAP with a 100-fold higher affinity (K D = 50 nm) compared to murine TAP (Ahn et al, 1996;Tomazin et al, 1996). Strikingly, ICP47 displays a 100-fold lower affinity to TAP solubilized in digitonin as reconstituted in membranes or membrane mimics (Aisenbrey et al, 2006;Eggensperger et al, 2014). When ICP47 binds to negatively charged lipid bilayers or detergent micelles, a transition of a mostly unstructured to a helix-loop-helix conformation is induced (Beinert et al, 1997;Pfänder et al, 1999).…”

Section: Viral Immune Evasionmentioning

confidence: 99%

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

Eggensperger

Tampé²

2015

Biological Chemistry

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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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An Annular Lipid Belt Is Essential for Allosteric Coupling and Viral Inhibition of the Antigen Translocation Complex TAP (Transporter Associated with Antigen Processing)

Cited by 27 publications

References 55 publications

A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex

A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex

Encapsulated membrane proteins: A simplified system for molecular simulation

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

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