Peptide-dependent tuning of major histocompatibility complex motional properties and the consequences for cellular immunity

Abstract

T cell receptors (TCRs) and other receptors of the immune system recognize peptides presented by class I or class II major histocompatibility complex (MHC) proteins. Although we generally distinguish between the MHC protein and its peptide, at an atomic level the two form a structural composite, which allows peptides to influence MHC properties and vice versa. One consequence is the peptide-dependent tuning of MHC structural dynamics, which contributes to protein structural adaptability and influences how receptors identify and bind targets. Peptide-dependent tuning of MHC protein dynamics can impact processes such as antigenicity, TCR cross-reactivity, and T cell repertoire selection. Motional tuning extends beyond the binding groove, influencing peptide selection and exchange, as well as interactions with other immune receptors. Here, we review recent findings showing how peptides can affect the dynamic and adaptable nature of MHC proteins. We highlight consequences for immunity and demonstrate how MHC proteins have evolved to be highly sensitive dynamic reporters, with broad immunological consequences.

Figure 1.

Peptide interactions with MHC proteins tune dynamics and conformational adaptability. (A) Hypothetical energy landscape of a class I peptide/MHC complex, with the crystallographic native state at the bottom of a traditional folding funnel, with conformation on the x-axis and energy on the y-axis. Zooming into the base of the funnel, which describes the crystallographically observed “ground state,” reveals variations in the energy landscape that lead to differential sampling of alternative conformations. Variations in the energy landscape arise from different interactions formed between peptides and the MHC protein. Panel adapted from ref. [33]. (B) Variation in peptide-MHC contacts in different structures. The figure tabulates counts of interactions between individual residues of the MHC and the peptide in 451 structures of human class I MHC proteins presenting nonameric or decameric peptides. An MHC residue was considered to be interacting with the peptide if any portion of that residue was within 4 Å of the peptide. The color and atomic radii of MHC atoms are proportional to the number of structures in which that residue makes an interaction with the peptide, as indicated by the scale at the bottom. Although there are several positions contacted in every structure (red spheres), there are also many where contacts vary between structures (blue/purple spheres). The nature of all contacts will vary with peptide sequence, as described in ref. [33]. (C) Heat maps of the peptide-MHC contacts in the 451 class I MHC crystal structures illustrating the counts of inter-residue contacts between peptide and MHC amino acids, shown for both nonameric and decameric peptides. Residues were considered to be in contact if any atoms were within 4 Å. The α helices of the MHC, as well as the residues which comprise the various pockets of the peptide binding groove [59], are identified. The color scale is as in panel B, with a maximum value of 353 for nonamers and 98 for decamers.

Figure 2.

Variance in atomic positions of amino acids comprising class I MHC α helices. (A) Positional Cα atomic variance for the α helices in crystal structures of free class I MHC proteins. Cα root mean square (RMS) fluctuations were calculated after superimposing the peptide binding grooves of 524 structures. These values were then mapped onto the α helices of a representative structure. Ribbon color and radius illustrates the fluctuations, with larger values being progressively more red and larger in radius. The α2-1 helix is particularly notable in its conformational variance. (B) Representative crystal structures which display large positional variances in the α2–1 helix. (C) Cα RMS fluctuations for 52 independent, 1 μs simulations of HLA-A2 presenting unique peptides calculated from a previously described molecular dynamics simulation library [50,60]. As in panel A, the residue color and radius of the helix at any position indicates the magnitude of RMS fluctuation.

Figure 3.

Differences in the variance of peptide presentation between class I and class II peptide/MHC complexes. Whereas peptides in class I complexes often bulge and tilt, this occurs far less frequently with class II complexes. (A) Top down and side views of 451 crystal structures of peptides presented by class I MHC proteins. (B) Top down and side views of 68 crystal structures of peptides presented by class II MHC proteins.