Venus flytrap or pas de trois? The dynamics of MHC class I molecules

Structural Models for Roseolovirus U20 And U21: Non-Classical MHC-I Like Proteins From HHV-6A, HHV-6B, and HHV-7

“…This could reflect bona fide aspects of U20 structure or conformational lability, but it is also possible that the U20 MHC platform and/or interdomain interaction might be stabilized by a binding partner. In conventional class Ia MHC proteins, peptide binding stabilizes the MHC platform and interdomain orientation, with synergistic stabilization by β2-microglobulin ( 84 , 85 ). However, we do not expect that U20 or U21 require β2-microglobulin or peptide to complete folding, as recombinant proteins that do not contain peptide or β2-microglobulin retain full biding activity, at least for HHV-6B U20 binding to ULBP-1 (GW and LJS, unpublished results) and HHV-7 U21 binding to the MHC-Ia molecule HLA-A2 ( 50 ).…”

Fast peptide exchange on major histocompatibility complex class I molecules by acidic stabilization of a peptide‐empty intermediate

“…Still, after all, we do not yet know which exact conformational rearrangement accompanies the M receptive ⇄ M non‐receptive transition of Equation 4 . It might be one of the movements of the binding site observed previously, 19 or else it might involve a movement of the α 1 / α 2 domain relative to the α 3 domain, or to β 2 m.…”

“…Measuring the k on separately from the k off requires an empty receptor, and since the binding site of empty wild type MHC‐I is natively unfolded and binds peptide only slowly (if at all), 19 , 20 , 21 , 22 , 23 , 24 , 25 we used empty disulfide‐stabilized MHC‐I (dsMHC‐I) molecules, which have a disulfide bond linking the α 1 and α 2 helices of the peptide‐binding groove, conformationally stabilizing the F pocket region in the absence of peptide in a structure that is close to the peptide‐bound state. 8 , 9 , 26 , 27 , 28 We first validated the use of dsA2 and dsA24 by repeating the exchange experiments, and we found that they exchange peptides significantly faster than their wild type (wt) counterparts and that they, importantly, show a similar dipeptide‐mediated and acidic acceleration of peptide exchange (Figure S1 ; Table S1 ).…”

“…This explanation is supported by our observation that the peptide‐empty form of A24 has a much higher T m (∆ T m = 7.5°C at pH 8) than empty A2 (Figure 4a). We have shown earlier that MHC‐I allotypes differ in the conformational stability of the empty form, and that this correlates with dependence on the conformational chaperone, tapasin 19,40,56 . However, A2 and A24 share a low tapasin dependence, 58 which suggests that the response of empty MHC‐I to acidic conditions, as encountered in the endosomes, is governed by a set of rules that are as yet unknown.…”

Homotypic and heterotypic in cis associations of MHC class I molecules at the cell surface

“…Finally, the term “open conformers” alludes to the venus flytrap structural model of peptide binding, in which the lateral helices of the peptide binding groove are hypothesized to open up outwards, away from each other, when no peptide is bound. In contrast to this simplistic static model, it is now known that the main property of peptide-empty class I molecules is the conformational fluctuation, or instability, of the peptide binding groove, which strongly depends on the allotype, and which may lead – on the average of conformational fluctuation – to an inward, outward, or no net movement of the helices ( Jantz-Naeem and Springer, 2021 ; Bouvier and Wiley, 1998 ; Kurimoto et al, 2013 ; Zacharias and Springer, 2004 ). Also, the term “open conformers” does not differentiate the Hβ and H species, which have very distinct biochemical properties ( Montealegre et al, 2015 ).…”