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.