Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes

  • 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) anThe 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.show moreshow less

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Metadaten
Author:Elisa Nurzia, Daniele Narzi, Alberto Cauli, Alessandro Mathieu, Valentina Tedeschi, Silvana Caristi, Rosa Sorrentino, Rainer A. Böckmann, Maria Teresa Fiorillo
URN:urn:nbn:de:bvb:29-opus-35759
Title of the journal / compilation:PLoS ONE 7.3 (2012): 09.10.2012 <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032865>
Document Type:Article
Language:English
Date of Publication (online):2012/10/09
Publishing Institution:Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Release Date:2012/10/09
SWD-Keyword:-
Original publication:PLoS ONE 7.3 (2012): 09.10.2012 <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032865>
Institutes:Naturwissenschaftliche Fakultät -ohne weitere Spezifikation-
Dewey Decimal Classification:570 Biowissenschaften; Biologie
Collections:Von der FAU geförderte Open Access Artikel 2012

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