Chang-Gonzalez Ana Cristina, Akitsu Aoi, Mallis Robert J, Lang Matthew J, Reinherz Ellis L, Hwang Wonmuk
Department of Biomedical Engineering, Texas A&M University, College Station, United States.
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, United States.
Elife. 2025 Apr 7;13:RP104280. doi: 10.7554/eLife.104280.
Increasing evidence suggests that mechanical load on the αβ T-cell receptor (TCR) is crucial for recognizing the antigenic peptide-bound major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination (Chang-Gonzalez et al., 2024). To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15 pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC and exhibits higher mechanical compliance during the simulation. These results indicate that the dynamic allostery common to the TCRαβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and nuanced biological outcomes.
越来越多的证据表明，αβT细胞受体（TCR）上的机械负载对于识别与抗原肽结合的主要组织相容性复合体（pMHC）分子至关重要。我们最近的全原子分子动力学（MD）模拟显示，TCR的结构域间运动负责TCR-pMHC复合物的负载诱导捕获键行为和肽段识别（Chang-Gonzalez等人，2024年）。为了进一步研究该机制的普遍性，我们在不同条件下对B7 TCR进行了全原子MD模拟，以便与我们之前对A6 TCR的模拟进行比较。这两种TCR识别相同的pMHC，并且在晶体结构中与pMHC具有相似的界面。我们发现，B7 TCR-pMHC界面在约15 pN的负载下通过一种保守的动态变构机制得以稳定，该机制涉及TCR框架的不对称运动。然而，尽管在晶体结构中B7与pMHC形成的接触与A6相当，但在模拟过程中，B7与pMHC的高占有率接触较少，并且表现出更高的机械顺应性。这些结果表明，TCRαβ框架共有的动态变构可以将界面接触中的细微差异放大为独特的机械响应和细微的生物学结果。
