HLA class I polymorphism has a dual impact on ligand binding and chaperone interaction

Hildebrand, William H.; Turnquist, Hēth; Prilliman, Kiley R.; Hickman, Heather D.; Schenk, Erin L.; McIlhaney, Mary M.; Solheim, Joyce C.

doi:10.1016/s0198-8859(02)00364-6

Cited by 38 publications

(32 citation statements)

References 33 publications

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“…Similar observations were also reported for tapasin-deficient cells (6). However, it should be noted that based on previous evidence of MHC I-specific differences in tapasin dependence, the extent and nature of post-ER stabilization may be allele-specific (36,37). Our studies suggest that post-ER stabilization of the tapasin-dependent allele HLA-B5 requires proprotein convertase (pPC) activity, but not endocytic recycling and/or endosomal processing (Fig.…”

Section: Discussionsupporting

confidence: 88%

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Leonhardt

Keusekotten

Bekpen

et al. 2005

The Journal of Immunology

103

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The transporter associated with Ag processing (TAP) translocates antigenic peptides into the endoplasmic reticulum for binding onto MHC class I (MHC I) molecules. Tapasin organizes a peptide-loading complex (PLC) by recruiting MHC I and accessory chaperones to the N-terminal regions (N domains) of the TAP subunits TAP1 and TAP2. To investigate the function of the tapasin-docking sites of TAP in MHC I processing, we expressed N-terminally truncated variants of TAP1 and TAP2 in combination with wild-type chains, as fusion proteins or as single subunits. Strikingly, TAP variants lacking the N domain in TAP2, but not in TAP1, build PLCs that fail to generate stable MHC I-peptide complexes. This correlates with a substantially reduced recruitment of accessory chaperones into the PLC demonstrating their important role in the quality control of MHC I loading. However, stable surface expression of MHC I can be rescued in post-endoplasmic reticulum compartments by a proprotein convertase-dependent mechanism.

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Section: Discussionsupporting

confidence: 88%

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Leonhardt

Keusekotten

Bekpen

et al. 2005

The Journal of Immunology

103

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“…Findings of peptide binding, x-ray diffraction, and thermodynamic studies are consistent with particular anchor residues interacting with different strengths on distinct subtypes (43)(44)(45), but systematic affinity measurements of shared ligands have not been performed with B27 subtypes. In addition, subtypes not associated with AS differ from the ASassociated subtypes by amino acid changes at positions that influence interactions with the peptide-loading complex, such as positions 114 and 116 (46)(47)(48)(49), raising the possibility that subtype-related differences in assisted loading may influence the overall stability of their peptide cargoes. Again, the influence of the B27 subtype differences in this process has not yet been addressed.…”

Section: Discussionmentioning

confidence: 99%

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Vázquez

Castro

2005

Arthritis & Rheumatism

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Objective. To determine whether the cell surface features of HLA-B27 subtypes reported to be differentially associated with ankylosing spondylitis (AS) differ in a way that correlates with disease susceptibility.Methods. Human cell transfectants expressing or lacking the transporter associated with antigen processing were used to determine the cell surface expression of B27 subtypes by flow cytometry with antibodies recognizing the B27 heterodimer or ␤ 2 -microglobulin (␤ 2 m)-free heavy chains.Results. In lymphoid cells with an intact peptideloading complex, all B27 subtypes, irrespective of their association with disease, showed similar ratios of free heavy chain to heterodimer, suggesting similar surface stability. A substantial decrease in dissociated heavy chains, which never reached 100%, was observed upon addition of a B27 ligand, with no significant differences among subtypes. This is compatible with similar surface expression of irreversible ␤ 2 m-free heavy chain forms among subtypes differentially associated with disease. In cells lacking the transporter associated with antigen processing, both disease-associated and non-diseaseassociated subtypes expressed a population of heterodimers at 26°C that was less stable than the population expressed at 37°C. In the presence of exogenous peptide, the expression of heterodimers increased, without a concomitant decrease in ␤ 2 m-free heavy chains. This suggests that in these cells, and for all subtypes tested, most of the dissociated heavy chains at the cell surface are in irreversible forms. At 37°C, the expression of ␤ 2 m-free B27 heavy chains was very low on T2 transfectant cells. Conclusion. HLA-B27 subtypes showing differential associations with AS are similar in their extent of ␤ 2 m dissociation and surface expression of free heavy chains.Class I major histocompatibility complex (MHC) proteins are heterodimers consisting of a polymorphic heavy chain that is noncovalently bound to ␤ 2 -microglobulin (␤ 2 m), a nonpolymorphic polypeptide. Assembly of MHC molecules takes place in the endoplasmic reticulum (ER), where they constitutively bind peptides. These arise mainly from proteasomal degradation in the cytosol, are transported into the lumen of the ER by means of the transporter associated with antigen processing (TAP), and bind, sometimes after trimming, to the class I molecule in a process involving several proteins collectively known as the peptide-loading complex (1). Peptides bound with sufficient affinity stabilize the native conformation of the nascent class I molecule. When this happens, the peptide-MHC complex is released from the ER and traffics to the cell surface. In cells lacking TAP, the peptide supply into the ER and the expression of class I MHC are drastically reduced. However, at 26°C, MHC molecules that are presumably devoid of peptide can be sufficiently stable to leave the ER and reach the cell surface (2).The ␤ 2 m-free class I MHC polypeptides are found at the cell surface. This can be revealed, for example, by cell surface stain...

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“…This attribute is not unique to APLP2 since MHC class I allele specificity is also exhibited by TAP, tapasin, and calreticulin (12)(13)(14)(15). Disparity among class I molecules in regard to chaperone dependence may provide protection against attack from viruses against any particular chaperone.…”

Section: Aplp2mentioning

confidence: 99%

“…Natural HLA molecules with limited amino acid changes in the ␣2 domain differ in respect to whether they associate with TAP (12). Certain HLA-A and -B subtypes strongly associate with TAP, tapasin, and calreticulin, while others differing only at a single amino acid residue show little to no association with these same proteins (13)(14)(15). Furthermore, the HLA subtypes that lack association with these ER proteins are more poorly retained and are present in greater quantity at the cell surface, indicating that differences in the ability of natural MHC heavy chains to interact with these ER proteins are functionally relevant (13)(14)(15).…”

mentioning

confidence: 99%

The Amyloid Precursor-like Protein 2 and the Adenoviral E3/19K Protein Both Bind to a Conformational Site on H-2Kd and Regulate H-2Kd Expression

Morris

Petersen

Vargas

et al. 2003

Journal of Biological Chemistry

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HLA class I polymorphism has a dual impact on ligand binding and chaperone interaction

Cited by 38 publications

References 33 publications

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

The Amyloid Precursor-like Protein 2 and the Adenoviral E3/19K Protein Both Bind to a Conformational Site on H-2Kd and Regulate H-2Kd Expression

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HLA class I polymorphism has a dual impact on ligand binding and chaperone interaction

Cited by 38 publications

References 33 publications

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

Similar cell surface expression of β2‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

The Amyloid Precursor-like Protein 2 and the Adenoviral E3/19K Protein Both Bind to a Conformational Site on H-2Kd and Regulate H-2Kd Expression

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Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis