Clusters of Structurally Similar MHC I HLA-A2 Molecules, Found with a New Method, Suggest Mechanisms of T‑Cell Receptor Avidity

Only α1 and α2 domains of the α-chain of the major histocompatibility complex (MHC) directly bind peptide antigens (Ag-s) and the T-cell receptor (TCR). Significant plasticity was found in the TCR but only minor in (α1 + α2). The α3-domain position variation was noted only in connection to its binding the coreceptor CD8. We apply our methods for identifying functional conformational changes in proteins to a systematic study of similarities between 43 X-ray structures of the entire α chains of MHC-I HLA-A2. Out of 903 different αHLA–A2 pairs 203 show similarities within the earlier determined uncertainty threshold and unexpectedly form three similarity clusters (SCs) with all/most structures in a cluster similar within the uncertainty threshold. Pairs from different SCs always differ above the threshold, mainly due to variations in the α3 position/structure. All structures in SC3 cannot bind the CD8 coreceptor. Strong hydrogen bonds between (α1 + α2) and α3 differ between SC1 and SC2 but are nearly invariant within each SC. Small conformational changes in the (α1 + α2), caused by Ag-s differences, act as an α3 “allosteric switch” between SC2 and SC1. Binding of CD8 to SC2-HLA-A2 (Tax-type Ag-s) changes it to SC1-HLA-A2 (HuD-type Ag-s). HuD binding to HLA-A2 is much less stable than Tax binding. CD8-liganded HLA-A2 preference for binding HuD suggests that CD8-HLA-A2 may present a weakly binding peptide for TCR recognition, supporting the hypothesis that CD8 increases TCR avidity to weak Ag-s. Other HLA-A2 functions may involve α3. TCR-A6-liganded-Tax-type-HLA-A2s form two small clusters, similar to either A6-liganded-HuD or A6-liganded-native-Tax HLA-A2s

Node centrality correlations.

<p>The median correlation for closeness centrality from <i>DCC</i>_<i>GNM</i> with <i>DCC</i>_<i>MD</i> is shown for different subsets of modes for all proteins. Vertical bars give values of standard errors.</p

Overlap between principal vectors from <i>DCC</i>_<i>GNM</i> with <i>DCC</i>_<i>MD</i>.

<p>The figure shows the extent of agreement between the residue cross-correlation matrices from MD and GNM in terms of the principal eigenvectors. The principal eigenvectors are obtained from singular value decomposition of the <i>DCC</i>_<i>GNM</i> and <i>DCC</i>_<i>MD</i> matrices, respectively. The median overlap between the vectors from MD and GNM, computed with RMSIP, is shown for subsets of 5, 10, 20, 30 and 50 modes. Vertical bars represent the standard errors in RMSIP.</p

Comparison of community structures for wild-type (PDB: 4s0w), stable (PDB: 3c81) and unstable (PDB: 3c82) mutant forms of T4 lysozyme.

<p>Three communities (green, brown and blue) are shown for each structure. <i>N</i>_<i>c</i> = 3 shows maximum structural difference between the community structures of mutant and wild-type forms, hence the choice. Coloring scheme is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199225#pone.0199225.g007" target="_blank">Fig 7</a>.</p

Variation of kappa coefficient with the number of modes.

<p>The figure shows the median <i>Kappa</i>_<i>max</i> for all proteins in the dataset for subsets including 5, 10, 20, 30 and 50 modes. Vertical bars represent the standard error of <i>Kappa</i>_<i>max</i>.</p

Community agreement for <i>unstable</i> (<i>red</i>) and <i>stable</i> (<i>blue</i>) mutants of T4 lysozyme with the wild-type.

<p>The figure shows the median kappa coefficient (agreement with wild-type) at each community level for the <i>unstable</i> and <i>stable</i> mutants. The communities were obtained with <i>DCC</i>_<i>GNM</i> calculated using (A) 5, (B) 10, (C) 20, (D) 30 and (E) 50 low-frequency modes. The abscissa and ordinates correspond to the number of communities and the Kappa coefficient respectively, as given in 6A.</p

Comparison of community structures for wild-type (PDB: 4s0w), stable (PDB: 3c8s) and unstable (PDB: 3c82) mutant forms of T4 lysozyme.

<p>Three communities (red, blue and green) are shown for each structure. <i>N</i>_<i>c</i> = 3 shows the maximum structural differences for the community structures in the mutant and wild-type forms, hence its choice. The coloring scheme is same as in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199225#pone.0199225.g007" target="_blank">7</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199225#pone.0199225.g008" target="_blank">8</a>.</p

Examples of C^α-distance maps and distance transformed dynamic cross-correlations from MD and GNM for <i>i</i>.

<p><b>Copper transporter domain from copper transporting ATPase (<i>top</i>), and <i>ii</i>. alpha-chymotrypsinogen (<i>bottom</i>).</b> For each protein, the figure shows the distance map for alpha-carbons (A and D), <i>dist_DCC</i>_<i>MD</i> (B and E) and <i>dist_DCC</i>_<i>GNM</i> (C and F). The color scale ranges from red (spatially distant regions and least correlated parts) to blue (regions in spatial proximity and most correlated parts). The PDB IDs of the structures used are 1fvq and 1cgi, for <i>i</i> and <i>ii</i> respectively. For ease of comparison with the C^α-distance maps, we use <i>dist_DCC</i> which has all values on a positive scale rather than <i>DCC</i> that has both positive and negative values.</p

Mutants for T4 Lysozyme sorted by <i>ΔΔG</i>.

<p>The set of PDB structures used to compare the community structure of stable and unstable mutants is given below. The Mutation column gives information on the mutation and has the format “xRy”, where ‘x’ is the residue in the wild-type, ‘y’ the residue in the mutant, and R is the position of mutation in the protein. More negative <i>ΔΔG</i> <b>values</b> indicate less stable mutant form.</p

Structure of the GroEL/GroES complex in (A) front and (B) top views.

<p>For subunits of the GroEL, the equatorial, intermediate, and apical domains of cis and <i>trans</i> rings are colored green, yellow, and blue, respectively. The GroES cap is displayed in red.</p