Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter

Powis, Simon J.; Townsend, Alain; Deverson, Edward V.; Bastin, Judy; Butcher, Geoffrey W.; Howard, Jonathan

doi:10.1038/354528a0

Cited by 319 publications

(182 citation statements)

References 27 publications

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“…This work represents the first structural imaging of the detergent-solubilized TAP ABC transporter, a transporter crucial to antigen presentation by MHC class I molecules, and the development of CD8ϩ T lymphocytes (10,12,66). The projection structure of TAP at low resolution is broadly comparable with that of other ABC transporters, P-glycoprotein, and MRP-1 (27,28).…”

Section: Discussionmentioning

confidence: 90%

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Velarde¹,

Ford²,

Rosenberg³

et al. 2001

Journal of Biological Chemistry

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The transporter associated with antigen processing (TAP) is an ATP binding cassette transporter responsible for peptide translocation into the lumen of the endoplasmic reticulum for assembly with major histocompatibility complex class I molecules. Immunoaffinity-purified TAP particles comprising TAP1 and TAP2 polypeptides, and TAP2 particles alone were characterized after detergent solubilization and studied by electron microscopy. Projection structures of TAP1؉2 particles reveal a molecule ϳ10 nm across with a deeply staining central region, whereas TAP2 molecules are smaller in projection. A three-dimensional structure of TAP reveals it is isolated as a single heterodimeric complex, with the TAP1 and TAP2 subunits combining to create a central 3-nm-diameter pocket on the predicted endoplasmic reticulum-lumenal side. Its structural similarity to other ABC transporters demonstrates a common tertiary structure for this diverse family of membrane proteins. ATP binding cassette (ABC)1 transporters are ubiquitous and can form a significant component of an organism's genome, for example 2% in Escherichia coli (1). They are defined by the ABC domain, a nucleotide hydrolysis domain whose activity powers substrate transport (2), and are classically composed of at least four domains, two transmembrane domains (TMDs) and two cytoplasmic and soluble nucleotide binding domains (NBDs). These domains can be expressed together as a single modular polypeptide or separately.TAP is an ABC transporter expressed in the endoplasmic reticulum (ER), which supplies peptides from the cytosol for binding by MHC class I molecules (3-8). In the absence of TAP the assembly of MHC class I and, consequently, antigen presentation are both severely impaired (9 -12). TAP is expressed as two polypeptide subunits, TAP1 and TAP2, each composed of one TMD and one NBD, which together form the functional transporter. Models for the predicted structure of TAP have relied on the sequence-based prediction of multiple transmembrane-spanning regions in the TMDs (13), the location of point mutations or naturally occurring polymorphisms affecting peptide selection and transport (14 -17), or the cytosolic or ER lumenal orientation of TAPs engineered to contain reporter molecules (18,19). More recently, expression of truncated TAP polypeptides suggests interactions between both the TMDs and NBDs of . Nevertheless, no direct structural imaging of this crucial molecule to the development of cellular immune responses has yet been obtained.There is a need for structural studies of whole ABC transporters to permit insights into their overall structure and functions. Single particle image analysis has successfully been applied to molecules of comparable size to TAP (23-26). Furthermore, low resolution electron microscopic structures of the ABC transporters P-glycoprotein and MRP1 have been determined using a combination of single particle and crystallographic analysis (27,28). Recently a structure for MsbA, a prokaryotic half-ABC transporter, has been published, all...

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Section: Discussionmentioning

confidence: 90%

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Velarde¹,

Ford²,

Rosenberg³

et al. 2001

Journal of Biological Chemistry

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“…Ubiquitinylation and proteolysis by proteasomes have been proposed as major candidates (Michalek et al, 1993;Dick et al, 1994;Rock et al, 1994). The resultant peptides are then translocated into the lumen of the RER by the transporter associated with antigen presentation (TAP) (Powis et al, 1991;Spies and DeMurs, 1991;Attaya et al, 1992). TAP is a heterodimer composed of two subunits (TAP1 and TAP2) located in the ER and cis-Golgi , and is responsible for the translocation of peptides of particular size and sequence (Androlewicz et al, 1993;Neefjes et al, 1993;Shepherd et al, 1993;Heemels and Ploegh, 1995).…”

mentioning

confidence: 99%

Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment.

Raposo

Santen

Leijendekker

et al. 1995

The Journal of Cell Biology

127

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Abstract. Misfolded membrane proteins are rapidly degraded, often shortly after their synthesis and insertion in the endoplasmic reticulum (ER), but the exact location and mechanisms of breakdown remain unclear. We have exploited the requirement of MHC class I molecules for peptide to achieve their correct conformation: peptide can be withheld by introducing a null mutation for the MHC-encoded peptide transporter, TAP. By withholding TAP-dependent peptides, the vast majority of newly synthesized class I molecules fails to leave the endoplasmic reticulum and is degraded. We used mice transgenic for HLA-B27 on a TAPl-deficient background to allow visualization by immunoelectron microscopy of misfolded HLA-B27 molecules in thymic epithelial cells. In such HLA transgenic animals, the TAP mutation can be considered a genetic switch that allows control over the extent of folding of the protein of interest, HLA-B27, while the rate of synthesis of the constituent subunits remains unaltered.,In TAPl-deficient, HLA-B27 transgenic animals, HLA-B27 molecules fail to assemble correctly, and do not undergo carbohydrate modifications associated with the Golgi apparatus, such as conversion to Endoglycosidase H resistance, and acquisition of sialic acids. We show that such molecules accumulate in an expanded network of tubular and fenestrated membranes. This compartment has its counterpart in normal thymic epithelial cells, and is identified as an ER-Golgi intermediate. We detect the presence of ubiquitin and ubiquitin-conjugating enzymes in association with this compartment, suggesting a nonlysosomal mode of degradation of its contents.

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“…This heterodimeric transport complex consists of TAP1 (ABCB2) and TAP2 (ABCB3) (Kleijmeer et al 1992;Lacaille and Androlewicz 1998). Both subunits are essential and sufficient for antigen processing (Powis et al 1991;Spies and DeMars 1991;Meyer et al 1994). …”

Section: The Tap Familymentioning

confidence: 99%

“…Therefore, the formation of dimers is essential for a functional transporter. TAP1, together with TAP2, forms an active transport complex (Powis et al 1991;Spies and DeMars 1991). TAP1 or TAP2 alone are not active in peptide binding and transport .…”

Section: Tapl Assembles Into a Functional Homodimeric Complexmentioning

confidence: 99%

TAP and TAP-like — Brothers in arms?

Zhao

Tampé

Abele

2006

Naunyn Schmied Arch Pharmacol

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The transporter associated with antigen processing like (TAPL, ABCB9) is a member of the ATP-binding cassette (ABC) transporter family. Moreover, TAPL belongs to the TAP family due to its high sequence homology to TAP1 and TAP2. TAPL forms a homodimer which is localized in lysosomes with a minor fraction in the ER. It functions as an ATP-dependent peptide transporter which shows a broad peptide specificity ranging from 6-mer up to 59-mer peptides. In contrast to TAP, TAPL transports peptides with low affinity but high efficiency. This review will briefly summarize current knowledge about the structural organization and possible physiological function of TAPL in antigen processing and presentation.

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Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter

Cited by 319 publications

References 27 publications

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment.

TAP and TAP-like — Brothers in arms?

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