ABCB3 p.Leu410Phe
| Predicted by SNAP2: | A: N (57%), C: N (57%), D: D (80%), E: D (75%), F: N (53%), G: D (63%), H: D (66%), I: N (82%), K: D (75%), M: N (61%), N: D (66%), P: D (80%), Q: D (66%), R: D (75%), S: D (53%), T: N (53%), V: N (93%), W: D (71%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[hide] The first N-terminal transmembrane helix of each s... FEBS Lett. 2006 Jul 24;580(17):4091-6. Epub 2006 Jun 30. Koch J, Guntrum R, Tampe R
The first N-terminal transmembrane helix of each subunit of the antigenic peptide transporter TAP is essential for independent tapasin binding.
FEBS Lett. 2006 Jul 24;580(17):4091-6. Epub 2006 Jun 30., [PMID:16828748]
Abstract [show]
The heterodimeric ABC transporter TAP translocates proteasomal degradation products from the cytosol into the lumen of the endoplasmic reticulum, where these peptides are loaded onto MHC class I molecules by a macromolecular peptide-loading complex (PLC) and subsequently shuttled to the cell surface for inspection by cytotoxic T lymphocytes. Tapasin recruits, as a central adapter protein, other components of the PLC at the unique N-terminal domains of TAP. We found that the N-terminal domains of human TAP1 and TAP2 can independently bind to tapasin, thus providing two separate loading platforms for PLC assembly. Moreover, tapasin binding is dependent on the first N-terminal transmembrane helix of TAP1 and TAP2, demonstrating that these two helices contribute independently to the recruitment of tapasin and associated factors.
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No. Sentence Comment
21 However, previous studies suggest that TAP and tapasin interact through their TMs, since soluble human tapasin variants and a transmembrane domain point mutant (L410F) were defective in TAP association and consequently impaired in MHC class I surface presentation [21].
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ABCB3 p.Leu410Phe 16828748:21:161
status: NEW[hide] A major role for tapasin as a stabilizer of the TA... Eur J Immunol. 2003 Jan;33(1):264-73. Garbi N, Tiwari N, Momburg F, Hammerling GJ
A major role for tapasin as a stabilizer of the TAP peptide transporter and consequences for MHC class I expression.
Eur J Immunol. 2003 Jan;33(1):264-73., [PMID:12594855]
Abstract [show]
Tapasin is a member of the MHC class I loading complex where it bridges the TAP peptide transporter to class I molecules. The main role of tapasin is assumed to be the facilitation of peptide loading and optimization of the peptide cargo. Here, we describe another important function for tapasin. In tapasin-deficient (Tpn(-/-)) mice the absence of tapasin was found to have a dramatic effect on the stability of the TAP1/TAP2 heterodimeric peptide transporter. Steady-state expression of TAP protein was reduced more than 100-fold from about 3 x 10(4) TAP molecules per wild-type splenocyte to about 1 x 10(2) TAP per Tpn(-/-) splenocyte. Thus, a major function of murine tapasin appears to be the stabilization of TAP. The low amount of TAP moleculesin Tpn(-/-) lymphocytes is likely to contribute to the severe impairment of MHC class I expression. Surprisingly, activation of Tpn(-/-) lymphocytes yielded strongly enhanced class I expression comparable to wild-type levels, although TAP expression remained low and in the magnitude of several hundred molecules per cell. The high level of class I on activated Tpn(-/-) cells depended on peptides generated by the proteasome as indicated by blockade with the proteasome-specific inhibitor lactacystin. Lymphocyte activation induced an increase in ubiquitinated proteins that are cleaved into peptides by the proteasome. These findings suggest that in the presence of a large peptide pool in the cytosol, a small number of TAP transporters is sufficient to translocate enough peptides for high class I expression. However, these class I molecules were less stable than those of wild-type cells, indicating that tapasin is not only required for stabilization of TAP but also for optimization of the spectrum of bound peptides.
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No. Sentence Comment
164 The interaction of tapasin with TAP appears to be mediated by the transmembrane (TM) region of tapasin, as suggested by a TM point mutant L410F of tapasin that fails to bind and stabilize TAP [4].
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ABCB3 p.Leu410Phe 12594855:164:138
status: NEW[hide] Tapasin-the keystone of the loading complex optimi... Mol Immunol. 2002 Oct;39(3-4):217-33. Momburg F, Tan P
Tapasin-the keystone of the loading complex optimizing peptide binding by MHC class I molecules in the endoplasmic reticulum.
Mol Immunol. 2002 Oct;39(3-4):217-33., [PMID:12200052]
Abstract [show]
MHC class I molecules are loaded with peptides that mostly originate from the degradation of cytosolic protein antigens and that are translocated across the endoplasmic reticulum (ER) membrane by the transporter associated with antigen processing (TAP). The ER-resident molecule tapasin (Tpn) is uniquely dedicated to tether class I molecules jointly with the chaperone calreticulin (Crt) and the oxidoreductase ERp57 to TAP. As learned from the study of a Tpn-deficient cell line and from mice harboring a disrupted Tpn gene, the transient association of class I molecules with Tpn and TAP is critically important for the stabilization of class I molecules and the optimization of the peptide cargo presented to cytotoxic T cells. The different functions of molecular domains of Tpn and the highly coordinated formation of the TAP-associated peptide loading complex will also be discussed in this review.
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No. Sentence Comment
164 Furthermore, the ER retention of hTpn-L410F was partially deficient, indicating that ER retention of Tpn is not a sole function of the canonical dilysine retention motif.
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ABCB3 p.Leu410Phe 12200052:164:38
status: NEW331 A functional defect in the association of HC/beta2m-Crt-Tpn with TAP is given in the presence of soluble Tpn, Tpn-L410F, or mTpn molecules in .220 cells as described above (Lehner et al., 1998; Tan et al., 2002).
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ABCB3 p.Leu410Phe 12200052:331:114
status: NEW334 We have recently shown that B*4402 molecules expressed in the presence of soluble hTpn, hTpn-L410F, or mTpn were suboptimally loaded with peptides (Tan et al., 2002).
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ABCB3 p.Leu410Phe 12200052:334:93
status: NEW165 Furthermore, the ER retention of hTpn-L410F was partially deficient, indicating that ER retention of Tpn is not a sole function of the canonical dilysine retention motif.
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ABCB3 p.Leu410Phe 12200052:165:38
status: NEW332 A functional defect in the association of HC/beta2m-Crt-Tpn with TAP is given in the presence of soluble Tpn, Tpn-L410F, or mTpn molecules in .220 cells as described above (Lehner et al., 1998; Tan et al., 2002).
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ABCB3 p.Leu410Phe 12200052:332:114
status: NEW335 We have recently shown that B*4402 molecules expressed in the presence of soluble hTpn, hTpn-L410F, or mTpn were suboptimally loaded with peptides (Tan et al., 2002).
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ABCB3 p.Leu410Phe 12200052:335:93
status: NEW[hide] Recruitment of MHC class I molecules by tapasin in... J Immunol. 2002 Feb 15;168(4):1950-60. Tan P, Kropshofer H, Mandelboim O, Bulbuc N, Hammerling GJ, Momburg F
Recruitment of MHC class I molecules by tapasin into the transporter associated with antigen processing-associated complex is essential for optimal peptide loading.
J Immunol. 2002 Feb 15;168(4):1950-60., [PMID:11823531]
Abstract [show]
The ER protein tapasin (Tpn) forms a bridge between MHC class I H chain (HC)/beta(2)-microglobulin and the TAP peptide transporter. The function of this TAP-associated complex was unclear because it was reported that soluble Tpn that has lost TAP interaction would be fully competent in terms of peptide loading and Ag presentation. We found, however, that only wild-type human Tpn (hTpn), but not three soluble hTpn variants, a transmembrane domain point mutant of hTpn (L410-->F), wild-type mouse Tpn, nor a mouse-human Tpn hybrid, fully up-regulated peptide-dependent Bw4 epitopes when expressed in Tpn-deficient.220.B*4402 cells. Consistent with suboptimal peptide loading, the t(1/2) of class I molecules was considerably reduced in the presence of soluble hTpn, hTpn-L410F, and murine Tpn. Furthermore, eluted peptide spectra and the class I-mediated inhibition of NK clones showed distinct differences to the hTpn transfectant. Only wild-type hTpn efficiently recruited HC and calreticulin (Crt) into complexes with TAP and endoplasmic reticulum p57 (ERp57). The L410F mutant was defective in TAP association, but bound to class I molecules, Crt, and ERp57. Mouse Tpn associated with human TAP and ERp57 on the one hand, and with HC and Crt on the other, but failed to recruit normal amounts of HLA class I molecules into the TAP complex. We conclude that the loading with peptides conferring high stability requires the Tpn-mediated introduction of HC into the TAP complex, whereas the mere interaction with Tpn is not sufficient.
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No. Sentence Comment
287 The novel TM point mutant L410F has essentially lost the capacity of wild-type Tpn to elevate TAP1 steady state levels.
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ABCB3 p.Leu410Phe 11823531:287:26
status: NEW289 The partial suspension of ER retention of the L410F mutant may have contributed to the failing stabilization of TAP.
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ABCB3 p.Leu410Phe 11823531:289:46
status: NEW290 The formation of complexes between Crt, hTpn-L410F, and HC (Fig. 5A) suggests, however, that the TM mutation did not significantly affect the interaction of Tpn with HC.
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ABCB3 p.Leu410Phe 11823531:290:26
status: NEWX
ABCB3 p.Leu410Phe 11823531:290:45
status: NEW327 In accordance with recent studies by the McCluskey group, who analyzed Kb - and B*2705-associated peptide spectra in the presence and absence of Tpn (12, 36), we noted a considerable overlap in the spectra derived from .220.B*4402 cells transfected with hTpn, mTpn, or hTpn-L410F.
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ABCB3 p.Leu410Phe 11823531:327:274
status: NEW292 The partial suspension of ER retention of the L410F mutant may have contributed to the failing stabilization of TAP.
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ABCB3 p.Leu410Phe 11823531:292:46
status: NEW293 The formation of complexes between Crt, hTpn-L410F, and HC (Fig. 5A) suggests, however, that the TM mutation did not significantly affect the interaction of Tpn with HC.
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ABCB3 p.Leu410Phe 11823531:293:45
status: NEW330 In accordance with recent studies by the McCluskey group, who analyzed Kb - and B*2705-associated peptide spectra in the presence and absence of Tpn (12, 36), we noted a considerable overlap in the spectra derived from .220.B*4402 cells transfected with hTpn, mTpn, or hTpn-L410F.
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ABCB3 p.Leu410Phe 11823531:330:274
status: NEW