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Aufsatz zugänglich unter
URN: urn:nbn:de:bvb:29-opus-35759
URL: http://www.opus.ub.uni-erlangen.de/opus/volltexte/2012/3575/
Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes
Nurzia, Elisa ;
Narzi, Daniele ;
Cauli, Alberto ;
Mathieu, Alessandro ;
Tedeschi, Valentina ;
Caristi, Silvana ;
Sorrentino, Rosa ;
Böckmann, Rainer A. ;
Fiorillo, Maria Teresa
| Originalveröffentlichung: |
| (2012) PLoS ONE 7.3 (2012): 09.10.2012 <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032865> |
| pdf-Format:
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| SWD-Schlagwörter: |
| - |
| Collection: |
| Universität Erlangen-Nürnberg / Von der FAU geförderte Open Access Artikel / 2012 |
| Fakultät: |
| Naturwissenschaftliche Fakultät |
| DDC-Sachgruppe: |
| Biowissenschaften, Biologie |
| Dokumentart: |
| Aufsatz |
| Sprache: |
| Englisch |
| Erstellungsjahr: |
| 2012 |
| Publikationsdatum: |
| 09.10.2012 |
| Kurzfassung in Deutsch: |
| The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL) and TIS (RRLPIFSRL), and the viral peptides pLMP2 (RRRWRRLTV) and NPflu (SRYWAIRTR). Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K) and non-conservative (R62A) B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype. |
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