Laboratory of Molecular Architecture, Media Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Int J Mol Sci. 2023 Nov 13;24(22):16266. doi: 10.3390/ijms242216266.
Chemokine receptors play crucial roles in fundamental biological processes. Their malfunction may result in many diseases, including cancer, autoimmune diseases, and HIV. The oligomerization of chemokine receptors holds significant functional implications that directly affect their signaling patterns and pharmacological responses. However, the oligomerization patterns of many chemokine receptors remain poorly understood. Furthermore, several chemokine receptors have highly truncated isoforms whose functional role is not yet clear. Here, we computationally show homo- and heterodimerization patterns of four human chemokine receptors, namely CXCR2, CXCR7, CCR2, and CCR7, along with their interaction patterns with their respective truncated isoforms. By combining the neural network-based AlphaFold2 and physics-based protein-protein docking tool ClusPro, we predicted 15 groups of complex structures and assessed the binding affinities in the context of atomistic molecular dynamics simulations. Our results are in agreement with previous experimental observations and support the dynamic and diverse nature of chemokine receptor dimerization, suggesting possible patterns of higher-order oligomerization. Additionally, we uncover the strong potential of truncated isoforms to block homo- and heterodimerization of chemokine receptors, also in a dynamic manner. Our study provides insights into the dimerization patterns of chemokine receptors and the functional significance of their truncated isoforms.
趋化因子受体在基本的生物学过程中起着至关重要的作用。它们的功能障碍可能导致许多疾病，包括癌症、自身免疫性疾病和 HIV。趋化因子受体的寡聚化具有重要的功能意义，直接影响它们的信号转导模式和药理学反应。然而，许多趋化因子受体的寡聚化模式仍未得到很好的理解。此外，一些趋化因子受体具有高度截断的同工型，其功能作用尚不清楚。在这里，我们通过计算的方法展示了四种人类趋化因子受体（即 CXCR2、CXCR7、CCR2 和 CCR7）及其与各自截断同工型的相互作用模式的同型和异型二聚体化模式。我们将基于神经网络的 AlphaFold2 和基于物理的蛋白质-蛋白质对接工具 ClusPro 相结合，预测了 15 组复杂结构，并在原子分子动力学模拟的背景下评估了结合亲和力。我们的结果与之前的实验观察结果一致，并支持趋化因子受体二聚化的动态和多样化性质，表明可能存在更高阶寡聚化的模式。此外，我们揭示了截断同工型以动态方式阻断趋化因子受体的同型和异型二聚化的强大潜力。我们的研究为趋化因子受体的二聚体化模式及其截断同工型的功能意义提供了深入的了解。
