Key Laboratory of Biorheology Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
Center of Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory), Beijing Key Laboratory of Engineered Construction and Mechanobiology, and CAS Center for Excellence in Complex System Mechanics, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China.
FEBS J. 2022 May;289(10):2877-2894. doi: 10.1111/febs.16303. Epub 2021 Dec 13.
Molecular-level selectin-cluster of differentiation 44 (CD44) interactions are far from clear because of the complexity and diversity of CD44 glycosylation and isoforms expressed on various types of cells. By combining experimental measurements and simulation predictions, the binding kinetics of three selectin members to the recombinant CD44 were quantified and the corresponding microstructural mechanisms were explored, respectively. Experimental results showed that the E-selectin-CD44 interactions mainly mediated the firm adhesion of microbeads under shear flow with the strongest rupture force. P- and L-selectins had similar interaction strength but different association and dissociation rates by mediating stable rolling and transient adhesions of microbeads, respectively. Molecular docking and molecular dynamics (MD) simulations predicted that the binding epitopes of CD44 to selectins are all located at the side face of each selectin, although the interfaces denoted as the hinge region are between lectin and epidermal growth factor domains of E-selectin, Lectin domain side of P-selectin and epidermal growth factor domain side of L-selectin, respectively. The lowest binding free energy, the largest rupture force and the longest lifetime for E-selectin, as well as the comparable values for P- and L-selectins, demonstrated in both equilibration and steered MD simulations, supported the above experimental results. These results offer basic data for understanding the functional differences of selectin-CD44 interactions.
由于 CD44 糖基化和各种细胞表达的异构体的复杂性和多样性，分子水平的选择素-分化簇 44（CD44）相互作用还远不清楚。通过结合实验测量和模拟预测，定量了三种选择素成员与重组 CD44 的结合动力学，并分别探索了相应的微观结构机制。实验结果表明，E-选择素-CD44 相互作用主要介导了在剪切流下微珠的牢固粘附，具有最强的断裂力。P-和 L-选择素通过分别介导微珠的稳定滚动和瞬时粘附，具有相似的相互作用强度但不同的结合和解离速率。分子对接和分子动力学（MD）模拟预测，CD44 与选择素的结合表位都位于每个选择素的侧面，尽管作为铰链区表示的界面分别位于 E-选择素的凝集素和表皮生长因子域、P-选择素的凝集素域侧和 L-选择素的表皮生长因子域侧。在平衡和引导 MD 模拟中，E-选择素的最低结合自由能、最大断裂力和最长寿命，以及 P-和 L-选择素的可比值，支持了上述实验结果。这些结果为理解选择素-CD44 相互作用的功能差异提供了基本数据。
