Chimeric SLA-1*1502/mβ2m/PP7 complex structure reveals distinct peptide binding, optimizing mouse models for immunological research.

Establishing accurate mouse models for immunological research, particularly those expressing heterologous Major Histocompatibility Complex class I (MHC-I) molecules, is crucial for understanding antigen presentation and T-cell responses. However, murine β2-microglobulin (mβ2m) can interfere with the proper folding and peptide loading of these heterologous heavy chains, potentially compromising model fidelity. This structural investigation addresses the molecular basis of this interference, aiming to refine strategies for creating more physiologically relevant models.

Researchers investigated the structural basis of SLA-1*1502 interaction with murine β2-microglobulin (mβ2m) and a Porcine reproductive and respiratory syndrome virus (PRRSV)-derived epitope peptide (PP7). They determined the crystal structure of the chimeric complex SLA-1*1502/mβ2m/PP7. This structure was then compared to the previously reported SLA-1*1502/sβ2m/PP7 complex (with swine β2m) to identify differences in heavy-light chain interactions and peptide binding modes. The primary endpoint was the atomic-level characterization of the complex stability and peptide presentation.

Murine β2-microglobulin (mβ2m) associated with SLA-1*1502 and the PP7 peptide to form a complex, albeit with lower efficiency compared to swine β2m (sβ2m). The crystal structure of the chimeric SLA-1*1502/mβ2m/PP7 complex revealed overall similar conformations to the sβ2m counterpart, but with distinct interaction patterns between the heavy and light chains, exhibiting features characteristic of both murine and porcine origins. Importantly, the peptide binding mode within the chimeric complex also showed unique local features: > The buried surface area between PP7 and the binding groove increased, and a new salt bridge formed between PP7 and residue R114 of SLA-1*1502. Structural comparisons across diverse cross-species chimeric complexes indicated that conformational shifts of bound epitope peptides are governed by the stability of the core hydrogen-bond network at the heavy-light chain interface. Substitution with human β2m triggered milder local structural distortions than murine β2m, highlighting the specific impact of mβ2m.