title: Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes.
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.affiliation: Department of Biology and Biotechnology C Darwin, Sapienza University, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nurzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Narzi
authors.forename: Alberto
authors.initials: A
authors.lastname: Cauli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mathieu
authors.forename: Valentina
authors.initials: V
authors.lastname: Tedeschi
authors.forename: Silvana
authors.initials: S
authors.lastname: Caristi
authors.forename: Rosa
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Rainer A
authors.initials: RA
authors.lastname: Böckmann
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Fiorillo
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine; D017124:Conserved Sequence; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry
chemical_list: C464936:HLA-B*27:05 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D012997:Solvents; D001120:Arginine