Assembly and Function of the Major Histocompatibility Complex (MHC) I Peptide-loading Complex Are Conserved Across Higher Vertebrates

Hinz, Andreas; Jedamzick, Johanna; Herbring, Valentina; Fischbach, Hanna; Hartmann, Jessica; Parcej, David; Koch, Joachim; Tampé, Robert

doi:10.1074/jbc.m114.609263

Cited by 17 publications

(16 citation statements)

References 36 publications

(42 reference statements)

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“…Unlike TAP, which is a promiscuous transporter found only in jawed vertebrates (Hinz et al, 2014), McjD and PCAT1 are dedicated to specific substrates. McjD exports microcin J25, a 21-residue antibacterial peptide with a lasso fold.…”

Section: Resultsmentioning

confidence: 99%

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

Oldham

Grigorieff

Chen

2016

eLife

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The transporter associated with antigen processing (TAP) is an ATP-binding cassette (ABC) transporter essential to cellular immunity against viral infection. Some persistent viruses have evolved strategies to inhibit TAP so that they may go undetected by the immune system. The herpes simplex virus for example evades immune surveillance by blocking peptide transport with a small viral protein ICP47. In this study, we determined the structure of human TAP bound to ICP47 by electron cryo-microscopy (cryo-EM) to 4.0 Å. The structure shows that ICP47 traps TAP in an inactive conformation distinct from the normal transport cycle. The specificity and potency of ICP47 inhibition result from contacts between the tip of the helical hairpin and the apex of the transmembrane cavity. This work provides a clear molecular description of immune evasion by a persistent virus. It also establishes the molecular structure of TAP to facilitate mechanistic studies of the antigen presentation process.DOI: http://dx.doi.org/10.7554/eLife.21829.001

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Section: Resultsmentioning

confidence: 99%

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

Oldham

Grigorieff

Chen

2016

eLife

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“…TmrA and tmrB were transferred to a mammalian expression system. TmrA was cloned into pcDXc3YCH and TmrB into pcDX (54). The TMD0 of human TAP2 (residues 1-127) was added seamlessly at the N terminus of TmrB.…”

Section: Methodsmentioning

confidence: 99%

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

Noll

Thomas

Herbring

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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108

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ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be regarded as a model system for asymmetric ABC exporters in general, and for TAP in particular.ABC transporter | conformational dynamics | membrane proteins | peptide transport | transporter associated with antigen processing

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“…All constructs were verified by DNA sequencing. ICP47 fragments of variable length (residues 1-35, 1-50, 1-65, 1-78, 1-88, or 12-88) were N-terminally fused to either coreTAP1 or coreTAP2 and transferred into the mammalian FX-expression vectors pcDXc3YCH (ICP47-TAP1 and ICP47-TAP2, for C-terminal mVenus-C8-His 10 tag) and pcDXc3CMS (ICP47-TAP2, for C-terminal mCerulean-myc-SBP tag)32. The ICP47-TAP fusion constructs for expression in human cells and subsequent orthogonal purification contained a tobacco etch virus (TEV) cleavage site between the ICP47 and coreTAP1 or coreTAP2.…”

Section: Methodsmentioning

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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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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Assembly and Function of the Major Histocompatibility Complex (MHC) I Peptide-loading Complex Are Conserved Across Higher Vertebrates

Cited by 17 publications

References 36 publications

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

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

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