Bano Fouzia, Banerji Suneale, Ni Tao, Green Dixy E, Cook Kalila R, Manfield Iain W, DeAngelis Paul L, Paci Emanuele, Lepšík Martin, Gilbert Robert J C, Richter Ralf P, Jackson David G
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Nat Commun. 2025 Mar 20;16(1):2754. doi: 10.1038/s41467-025-57866-8.
Immune surveillance involves the continual migration of antigen-scavenging immune cells from the tissues to downstream lymph nodes via lymphatic vessels. To enable such passage, cells first dock with the lymphatic entry receptor LYVE-1 on the outer surface of endothelium, using their endogenous hyaluronan glycocalyx, anchored by a second hyaluronan receptor, CD44. Why the process should require two different hyaluronan receptors and by which specific mechanism the LYVE-1•hyaluronan interaction enables lymphatic entry is however unknown. Here we describe the crystal structures and binding mechanics of murine and human LYVE-1•hyaluronan complexes. These reveal a highly unusual, sliding mode of ligand interaction, quite unlike the conventional sticking mode of CD44, in which the receptor grabs free hyaluronan chain-ends and winds them in through conformational re-arrangements in a deep binding cleft, lubricated by a layer of structured waters. Our findings explain the mode of action of a dedicated lymphatic entry receptor and define a distinct, low tack adhesive interaction that enables migrating immune cells to slide through endothelial junctions with minimal resistance, while clinging onto their hyaluronan glycocalyx for essential downstream functions.
免疫监视涉及抗原清除免疫细胞通过淋巴管从组织持续迁移至下游淋巴结。为实现这种迁移，细胞首先利用其由第二个透明质酸受体CD44锚定的内源性透明质酸糖萼，与内皮外表面的淋巴进入受体LYVE-1对接。然而，该过程为何需要两种不同的透明质酸受体，以及LYVE-1与透明质酸的相互作用通过何种具体机制实现淋巴进入尚不清楚。在此，我们描述了小鼠和人LYVE-1与透明质酸复合物的晶体结构及结合机制。这些结构揭示了一种非常独特的配体相互作用滑动模式，与CD44的传统黏附模式截然不同，在CD44的传统黏附模式中，受体抓住游离的透明质酸链端，并通过在一个由一层结构化水润滑的深结合裂隙中的构象重排将它们缠绕进去。我们的研究结果解释了一种专门的淋巴进入受体的作用方式，并定义了一种独特的、低黏附性的黏附相互作用，这种相互作用使迁移的免疫细胞能够以最小的阻力滑过内皮连接，同时附着在其透明质酸糖萼上以实现重要的下游功能。
