Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes.

Nurzia E, Narzi D, Cauli A, Mathieu A, Tedeschi V, Caristi S, Sorrentino R, Böckmann R, Fiorillo MT (2012)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2012

Journal

PLoS ONE Public Library of Science

Publisher: Public Library of Science

Book Volume: 7

Pages Range: e32865

Volume: 7

Issue: 3

Journal Issue: 3

DOI: 10.1371/journal.pone.0032865

Abstract

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.

Authors with CRIS profile

Daniele Narzi Professur für Computational Biology Rainer Böckmann Professur für Computational Biology

Involved external institutions

Università degli studi "La Sapienza" IT Italy (IT) Università degli Studi di Cagliari IT Italy (IT)

How to cite

APA:

Nurzia, E., Narzi, D., Cauli, A., Mathieu, A., Tedeschi, V., Caristi, S.,... Fiorillo, M.T. (2012). Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes. PLoS ONE, 7(3), e32865. https://dx.doi.org/10.1371/journal.pone.0032865

MLA:

Nurzia, Elisa, et al. "Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes." PLoS ONE 7.3 (2012): e32865.

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