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Tapasin discriminates peptide-human leukocyte antigen-A*02:01 complexes fromed with natural ligands

Roder, Gustav; Geironson Ulfsson, Linda LU ; Rasmussen, Michael; Harndahl Nord, Mikkel; Buus, Sören and Paulsson, Kajsa M LU (2011) In Journal of Biological Chemistry 286(23). p.20547-20557
Abstract
A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn(1-87), assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to... (More)
A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn(1-87), assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to established tapasin dependence hierarchies. Two large sets of HLA-A*02:01 binding peptides, one extracted from natural HLA-I ligands from the SYFPEITHI database and one consisting of medium to high affinity non-SYFPEITHI ligands, were studied in the context of HLA-A*02:01 binding and stability. We show that the SYFPEITHI peptides induced more stable HLA-A*02:01 molecules than the other ligands, although affinities were similar. Remarkably, Tpn(1-87) could functionally discriminate the selected SYFPEITHI peptides from the other peptide binders with high sensitivity and specificity. We suggest that this HLA-I- and peptide-specific function, together with the functions exerted by the more C-terminal parts of tapasin, are major features of tapasin-mediated HLA-I quality control. These findings are important for understanding the biogenesis of HLA-I molecules, the selection of presented T-cell epitopes, and the identification of immunogenic targets in both basic research and vaccine design. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antigen presentation, Antigen processing, Chaperone chaperonin, MHC, Peptides, Tapasin
in
Journal of Biological Chemistry
volume
286
issue
23
pages
20547 - 20557
publisher
ASBMB
external identifiers
  • wos:000291267600041
  • scopus:79957972468
ISSN
1083-351X
DOI
10.1074/jbc.M111.230151
language
English
LU publication?
yes
id
5d385238-1b4f-43fb-b8d2-cf65f07d7aeb (old id 2438664)
date added to LUP
2012-04-20 12:54:02
date last changed
2017-08-27 03:14:34
@article{5d385238-1b4f-43fb-b8d2-cf65f07d7aeb,
  abstract     = {A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn(1-87), assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to established tapasin dependence hierarchies. Two large sets of HLA-A*02:01 binding peptides, one extracted from natural HLA-I ligands from the SYFPEITHI database and one consisting of medium to high affinity non-SYFPEITHI ligands, were studied in the context of HLA-A*02:01 binding and stability. We show that the SYFPEITHI peptides induced more stable HLA-A*02:01 molecules than the other ligands, although affinities were similar. Remarkably, Tpn(1-87) could functionally discriminate the selected SYFPEITHI peptides from the other peptide binders with high sensitivity and specificity. We suggest that this HLA-I- and peptide-specific function, together with the functions exerted by the more C-terminal parts of tapasin, are major features of tapasin-mediated HLA-I quality control. These findings are important for understanding the biogenesis of HLA-I molecules, the selection of presented T-cell epitopes, and the identification of immunogenic targets in both basic research and vaccine design.},
  author       = {Roder, Gustav and Geironson Ulfsson, Linda and Rasmussen, Michael and Harndahl Nord, Mikkel and Buus, Sören and Paulsson, Kajsa M},
  issn         = {1083-351X},
  keyword      = {Antigen presentation,Antigen processing,Chaperone chaperonin,MHC,Peptides,Tapasin},
  language     = {eng},
  number       = {23},
  pages        = {20547--20557},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Tapasin discriminates peptide-human leukocyte antigen-A*02:01 complexes fromed with natural ligands},
  url          = {http://dx.doi.org/10.1074/jbc.M111.230151},
  volume       = {286},
  year         = {2011},
}