HLA-B27 Subtypes Differentially Associated with Disease Exhibit Conformational Differences in Solution

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

“…Although the structural analysis suggests similar behavior with the murine class I MHC H-2K b , an important question to resolve is whether and how MHC micropolymorphisms influence the peptide dependence of dynamics. This may be particularly likely for polymorphic positions whose side chains are embedded within the peptide-binding groove (15). Less clear is the extent to which peptide-dependent dynamics occur in class II MHC proteins.…”

“…Indeed, with HLA-A2, the mobility of the region that undergoes a structural change upon binding of the A6 TCR was shown to vary with different peptides (10). This may not be a unique observation as similar effects are believed to contribute to differential T cell recognition of native and modified MART-1 peptides (6), and MHC flexibility can be altered by micropolymorphisms (7,14,15). As demonstrated by the A6 TCR, peptide-dependent MHC dynamics can impact TCR recognition by altering the barriers for conformational adjustments, influencing the entropic costs for receptor binding and shifting the populations of binding-competent states.…”

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

“…Therefore, the structural data suggest that it is the dual peptide binding mode in the B*27:05 subtype which leads to inappropriate selection of T cells within the thymus. We regard it as most likely that pVIPR is not statically bound to this subtype (there is some indirect support for this assumption, see Narzi et al (2008) and Fabian et al (2008)) and that CTL are "irritated" by the most likely extremely unusual dynamics exhibited by this peptide. This may result in "erroneous" survival of pVIPR-B*27:05-directed CTL.…”

“…For IR spectroscopy, the light chain of MHC class I complexes, β 2 m, was labelled in vivo with 13 C and then complexed with unlabelled HLA-B27 HC and selected peptides in vitro ( [Fabian et al, 2008], [Fabian et al, 2010] and [Fabian et al, 2011]). Conversely, for fluorescence spectroscopic experiments, unlabelled HLA-B27 HC and β 2 m were reconstituted with peptides carrying a fluorescent marker ( [Pöhlmann et al, 2004], , [Winkler et al, 2007] and [Narzi et al, 2008]). …”

“…We also determined the first structure (Hülsmeyer et al, 2005a) of an MHC molecule in complex with a recombinant mAb exhibiting peptide-specific reactivity (Chames et al, 2000). Furthermore, we found that the intrinsic flexibility of the B*27:05 heavy chain (HC) is independent of both the sequence as well as the conformation of a bound peptide, but is more pronounced than that exhibited by the HC of the B*27:09 subtype ( [Fabian et al, 2008], [Fabian et al, 2010] and [Fabian et al, 2011]). These are the first results that reveal a correlation between dynamic properties of MHC molecules and a disease.…”