Do Hung N, Zhao Mingfei, Alam S Munir, Gnanakaran S
Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL, 35487, USA.
Commun Biol. 2025 Feb 13;8(1):226. doi: 10.1038/s42003-025-07478-1.
B-cell receptor (BCR) complexes are expressed on the surface of a B-cell and are critical in antigen recognition and modulating the adaptive immune response. Even though the relevance of antibodies has been known for almost a hundred years, the antigen-dependent activation mechanism of B-cells has remained elusive. Several models have been proposed for BCR activation, including cross-linking, conformation-induced oligomerization, and dissociation activation models. Recently, the first cryo-EM structures of the human B-cell antigen receptor of the IgM and IgG isotypes have been published that validates the asymmetric organization of the BCR complex. Here, we carry out extensive molecular dynamics simulations to probe the conformational changes upon antigen binding and the influence of the membrane lipids. We identify two critical dynamical events that could be associated with antigen-dependent activation of BCR. First, antigen binding causes increased flexibility in regions distal to the antigen binding site. Second, antigen binding alters the rearrangement of IgM transmembrane helices, including the relative interaction of Igα/Igβ that mediates intracellular signaling. Furthermore, these transmembrane rearrangements lead to changes in localized lipid composition. Our work indirectly supports the conformational-change induced models of BCR activation and contributes to the understanding of the antigen-dependent activation mechanism of BCRs.
B细胞受体（BCR）复合物表达于B细胞表面，在抗原识别和调节适应性免疫反应中起关键作用。尽管抗体的相关性已为人所知近百年，但B细胞的抗原依赖性激活机制仍不清楚。针对BCR激活已提出了几种模型，包括交联、构象诱导寡聚化和解离激活模型。最近，已发表了IgM和IgG同种型的人B细胞抗原受体的首批冷冻电镜结构，证实了BCR复合物的不对称组织。在此，我们进行了广泛的分子动力学模拟，以探究抗原结合后的构象变化以及膜脂的影响。我们确定了两个可能与BCR的抗原依赖性激活相关的关键动力学事件。第一，抗原结合导致抗原结合位点远端区域的灵活性增加。第二，抗原结合改变了IgM跨膜螺旋的重排，包括介导细胞内信号传导的Igα/Igβ的相对相互作用。此外，这些跨膜重排导致局部脂质组成的变化。我们的工作间接支持了BCR激活的构象变化诱导模型，并有助于理解BCR的抗原依赖性激活机制。
